Skip to main content
PMC home page
International Journal of Molecular Sciences logoLink to International Journal of Molecular Sciences
. 2020 Dec 2;21(23):9208. doi: 10.3390/ijms21239208

The Cellular Prion Protein: A Promising Therapeutic Target for Cancer

Gyeongyun Go 1, Sang Hun Lee 1,2,*
PMCID: PMC7730109  PMID: 33276687

Abstract

Studies on the cellular prion protein (PrPC) have been actively conducted because misfolded PrPC is known to cause transmissible spongiform encephalopathies or prion disease. PrPC is a glycophosphatidylinositol-anchored cell surface glycoprotein that has been reported to affect several cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also been reported that PrPC mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrPC regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrPC promotes tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In addition, we discuss strategies to treat tumors by modulating the function and expression of PrPC via the regulation of HSPA1L/HIF-1α expression and using an anti-prion antibody.

Keywords: cellular prion protein, PrPC, PRNP, cancer, cancer stem cell, targeted cancer therapy

1. Introduction

The cellular prion protein (PrPC) is a cell surface glycophosphatidylinositol (GPI)-anchored protein consisting of 208 amino acids, and it is encoded by the PRNP gene located on chromosome 20. PrPC has been intensively studied since it was proposed that misfolding of PrPC plays a key role in the pathogenesis of neurodegenerative diseases called transmissible spongiform encephalopathies [1,2,3]. Studies have shown that PrPC is not simply a cause of neurodegenerative diseases, but it is an important protein involved in many cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation [4,5,6,7,8,9,10]. Furthermore, several studies have shown that PrPC expression is associated with tumor progression [11,12,13,14,15]. Before addressing the role of PrPC in tumor progression, we briefly introduce herein some biochemical aspects of PrPC.

PrPC is first synthesized as a precursor protein (pre-pro-PrP) comprising 253 amino acids with a signal peptide at the N-terminus and a GPI anchor peptide signaling sequence (GPI-PSS) at the C-terminus. The signal peptide directs pre-pro-PrP into the endoplasmic reticulum (ER), wherein it is cleaved to generate pro-PrP. The pro-PrP is then translocated from the ER to the Golgi complex [16,17] to be further processed by the addition of N-linked glycans, removal of the GPI-PSS, and addition of the pre-assembled GPI anchor [18,19]. Finally, the mature PrPC of 208 amino acids is translocated to the outer membrane leaflet of cells. However, not all PrPCs are present on the cell surface. They are constantly internalized through the recycling endosome and trafficked back repeatedly [20,21,22]. Through this recycling process, PrPCs are also found in the Golgi [22,23], in addition to the nucleus [24,25] and mitochondria [26,27].

The relationship between PrPC and cancer progression was first discovered when PRNP was identified as one of the most-expressed genes in pancreatic cancer cells [28]. Around the same time, other researchers found that PrPC was overexpressed in a drug-resistant cancer cell line compared to the parental cell line [29]. Based on several studies, it is now well established that PrPC is involved in the main aspects of cancer biology: proliferation, metastasis, and drug resistance. Moreover, the relationship between PrPC and cancer stem cell phenotypes has also been uncovered [30,31]. In this review, we summarize the role of PrPC in tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. Finally, we discuss strategies to control tumor growth by regulating the function and expression of PrPC.

2. Overview of Physiological Functions of PrPC

PrPC is known to regulate several functions of cells, such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. In this review, we briefly summarize the effects of PrPC on stress protection, cellular differentiation, and mitochondrial homeostasis.

Several studies have shown that PrPC can directly inhibit apoptosis. PrPC expression inhibited mitochondria-dependent apoptosis in Bax-overexpressing human primary neurons and MCF-7 breast cancer cells [32,33]. In addition, downregulation of PrPC reduced the viability of MDA-MB-435 breast cancer cells after serum deprivation [34]. In primary hippocampal neurons, PrPC protected the cells against staurosporine-induced cell death by interacting with stress-induced phosphoprotein 1 (STI1) [35,36,37]. PrPC is also known to protect cells from oxidative stress. For example, the basal levels of ROS and lipid peroxidation were lower in PrPC-transfected neuroblastoma and epithelial cell lines than in untransfected controls [38,39]. In addition, the expression of PrPC by primary neurons and astrocytes has been associated with lower levels of damage caused by the addition of various oxidative toxins such as xanthine oxidase, kainic acid, and hydrogen peroxide [40,41]. PrPC has also been found to be involved in the ER-stress response. When breast carcinoma cells were treated with the ER-stress inducing compounds such as brefeldin A, tunicamycin, and thapsigargin, the expression of PrPC was induced. Downregulation of PrPC in several cancer cell lines resulted in an increase in cell death in response to these toxins [13].

Neurite outgrowth is one of the characteristics of neuronal differentiation. Several studies have indicated that PrPC promotes neurite outgrowth through interactions with other proteins such as neural cell adhesion molecule 1, epidermal growth factor receptor, integrins, laminin, and STI1 [35,42,43,44,45]. The downstream signaling of these interactions may include RhoA-Rho kinase-LIMK-cofilin pathway [44]. Activation of various signal pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs), may also induce PrPC-dependent neurite outgrowth [35,43,46]. It has been reported that PrPC is also involved in the differentiation of embryonic stem cells. In human embryonic stem cells, downregulation of PrPC delays spontaneous differentiation into the three germ layers [47]. Similarly, PrPC expression promotes the differentiation of cultured human embryonic stem cells and multipotent neural precursors to mature neurons, astroglia, and oligodendroglia [47,48].

PrPC expression also affects mitochondrial homeostasis. Transcriptomic and proteomic analyses of brain tissues and neurons of PrPC-null and wild-type mice have identified differently expressed proteins. These proteins include cytochrome c oxidase subunits 1 and 2, which are involved in oxidative phosphorylation [49,50]. Furthermore, the absence of PrPC reduces the number of total mitochondria and increases the number of mitochondria with unusual morphology [49].

3. PrPC and Cancer Proliferation

PrPC expression has been reported to promote cancer proliferation in several types of cancer cells, including gastric [51], pancreatic [52], and colon [53,54,55], as well as in glioblastoma (GBM) [56,57] and schwannanoma [58].

In gastric cancer, PrPC promotes cell proliferation and metastasis of cancer cells and promotes tumor growth in xenograft mouse models [51]. PrPC increases the expression of cyclin D1 and thereby promotes their transition from the G0/G1 phase to the S-phase. PrPC expression also affects Akt signaling. Overexpression of PrPC increases p-Akt levels, whereas PrPC knockdown inhibits p-Akt expression [59]. Interestingly, it is known that certain regions of PrPC influence cell proliferation. Specifically, deletion of amino acids 24–50 of PrPC significantly reduced cell proliferation. Conversely, deletion of amino acids 51–91 did not affect apoptosis, metastasis cell proliferation, and multidrug resistance in gastric cancer [60].

In pancreatic ductal adenocarcinoma (PDAC), expression of PrPC increases the proliferation and migration of the cells. In PDAC cell lines, PrPC exists as a pro-PrP as it retains its GPI-PSS, which has a filamin A (FLNA) binding motif. It was found that the interaction between pro-PrP and FLNA, a cytoplasmic protein involved in actin organization, promotes cell migration [61]. In addition, other studies have shown that PrPC promote pancreatic cell proliferation by activating the Notch signaling pathway [62].

PrPC is known to interact with other membrane proteins or extracellular molecules to perform various cellular functions. In human GBM, PrPC and heat shock 90/70 organizing protein (HOP) are upregulated, and their expression levels correlate with higher proliferation rates and poorer clinical outcomes [56]. Additionally, it has been demonstrated that the binding of HOP to PrPC promotes proliferation of GBM cell lines and that disruption of PrPC–HOP interaction inhibits tumor growth and improves the survival of mice [56].

In DLS-1 and SW480 colorectal cancer cells, knockdown of PrPC significantly reduces the proliferation of cancer cells. It is known that the binding between HIF-2α and the GLUT1 promoter region decreases when PrPC expression is suppressed, resulting in a decrease in the expression of GLUT1. This may reduce glucose uptake and glycolysis and inhibit cell proliferation [54].

4. PrPC and Metastasis

It has been demonstrated that PrPC promotes the invasion and migration of several types of cancer cells, such as gastric [63], pancreatic [62], colon [64], and melanoma [65] cells.

PrPC expression is higher in metastatic gastric cancer than in non-metastatic gastric cancer. PrPC increases the invasion and in vivo metastatic ability of gastric cancer cell lines SGC7901 and MKN45, and knockdown of PrPC significantly reduces cancer cell invasion [63]. PrPC seems to induce cancer cell invasion by activating the p-ERK1/2 signal and inducing the expression of MMP11. Interestingly, the N-terminal fragment (amino acids 24–90) of PrPC has been proposed as the region for its invasion-promoting function.

PrPC levels were found to increase in invasive melanoma, whereas in normal melanocytes, PrPC was not detected [65]. In melanoma, PrPC is known to exist as pro-PrP, retaining its GPI-PSS with an FLNA binding motif. As in PDAC earlier, PrPC promoted migration by binding with FLNA and regulating cytoskeleton organization. PrPC knockdown significantly reduced the migration of melanoma cells in a wound healing assay [65,66].

In colon cancer, PrPC is known to promote migration by binding to HOP, also known as stress-induced phosphoprotein 1 (STI1) [64]. It was found that among the colon primary tumor cells, only PrPC-positive cells were able to promote liver metastasis after injection into immunocompromised mice [67]. Metastasis is highly correlated with epithelial-mesenchymal transition (EMT), a process in which cells lose epithelial markers and interaction between the cell and the extracellular matrix change the cytoskeleton organization and differentiate into mesenchymal phenotype [68]. It is well known that transcription factors such as SNAI1, SNAI2, TWIST1, TWIST2, ZEB1, and ZEB2 induce EMT. PRNP expression is highly associated with the EMT signature in colon cancer patients, and PrPC is known to control the expression of ZEB1 in colon cancer cells [53].

5. PrPC and Drug Resistance

PrPC levels were found to be higher in tumor necrosis factor α (TNF-α)-resistant breast cancer cells than in TNF-α-sensitive breast cancer cells [33]. After treatment of TNF-α, the resistant cells did not exhibit cytochrome c release or nuclear condensation. Moreover, PrPC expression inhibited the Bax translocation to mitochondria and Bax-mediated cytochrome c release. In addition to TNF-α, PrPC is also involved in the resistance to adriamycin (ADR) and TRAIL-mediated cell death in breast cancer cells as down-regulation of PrPC increased the sensitivity to these molecules. [69]. Inhibition of PrPC expression did not inhibit formation of death-inducing signaling complex (DISC); however, it inhibited Bcl-2 expression and promoted Bid cleavage, resulting in cell death [69]. In addition, it has been confirmed that PrPC co-localization and coexpression with p-glycoprotein (P-gp) occur in ADR-resistant MCF-7 cells. When the expression of PrCC was inhibited in these cells, the capability of paclitaxel, a P-gp substrate, to induce in vitro invasion of the cells decreased [52]. More importantly, tissue microarray analysis of 756 breast cancer tumors demonstrated that PrPC was associated with ER-negative breast cancer subsets, and compared with ER-negative/PrPC-positive cells, ER-negative/PrPC-negative cells are more sensitive to adjuvant chemotherapy [70].

PrPC is also involved in drug resistance in colon cancer. Hypoxia-induced PrPC expression in colorectal cancer cells inhibits TRAIL-induced apoptosis [71]. PrPC inhibited apoptosis of colon cancer cells by activating the PI3K-Akt pathway [72]. Conversely, deletion of PrPC resulted in reduced Akt activation and enhanced caspase-3 activation [73]. Our group has demonstrated that PrPC levels significantly increase in 5-FU-and oxaliplatin-resistant colorectal cancer [74,75,76,77]. In addition, knocking down PrPC expression significantly reduces the drug resistance of colorectal cancer cells. Furthermore, we have shown that PrPC suppresses the drug-induced activation of stress-associated proteins, such as p38, JNK, and p53. We have also demonstrated that PrPC inhibits caspase-3 activation by drugs and PARP1 cleavage. These results suggest that the level of PrPC plays an important role in the development of drug resistance in colorectal cancer cells.

6. PrPC and Cancer Stem Cells

Cancer stem cells (CSCs) are a subpopulation of cells that are capable of self-renewal, differentiation into various cell types in a determined tumor, and tumor propagation when xenotransplanted into mice [78,79]. CSCs are resistant to conventional medical therapies and have been implicated in cancer recurrence, which has made these cells a key target for therapy [80,81,82].

Recently, studies on the correlation between PrPC and CSCs have been conducted. PrPC activation of Fyn-SP1 pathway in colon cancer cells promoted EMT and resulted in a more aggressive phenotype [83]. EMT is closely connected with CSC properties as EMT enhances metastasis and drug resistance of cancer and cancer microenvironment promotes activation of EMT program [84]. Du et al. demonstrated that PrPC-positive primary colon cancer cells expressed high levels of the EMT-associated markers, TWIST and N-cadherin, and low levels of the epithelial marker, E-cadherin, as well as exhibiting CSC properties such as the expression of the CSC marker, CD44, and tumor-initiating capacity [67].

In line with this finding, PrPC has been shown to interact with CD44 in multidrug-resistant breast cancer cells [85]. Furthermore, in primary GBM cells, PrPC silencing reduces the expression of the CSC markers, Sox2 and Nanog, as well as the self-renewal and tumorigenic potential of CSCs [57]. Similar findings were demonstrated by Iglesia et al., who worked on GBM cell lines grown as neurospheres [86].

CSCs are one of the most-studied recent topics in cancer biology. They have emerged as pivotal components that can initiate and maintain tumors [79]. PrPC is known to interact with CD44, and its expression correlates with resistance to chemotherapy in breast cancer cell lines [85]. Moreover, the CD44-positive and PrPC-positive subpopulations of colorectal tumor cells have CSC properties, including tumorigenic and metastatic capacities [67], indicating that PrPC contributes to tumor maintenance by modulating CSC behaviors.

Our group confirmed the correlation between PrPC and CSC by demonstrating that the levels of PrPC and CSC marker proteins such as Oct4, Nanog, Sox2, and ALDH1A1 significantly increased in human colorectal cancer tissues and colorectal cancer cells [31]. In addition, knockdown of PrPC reduced the expression of CSC markers in the CSCs. More specifically, PrPC inhibited the anticancer drug-induced degradation of Oct4, but did not inhibit the degradation of other stem cell markers such as Nanog, Sox2, and ALDH1A1. Oct4 is a master regulator involved in the self-renewal and pluripotency of CSCs. It has been reported that tumor sphere formation ability is activated in breast cancer cells overexpressing Oct4 [87,88]. Cancer cells overexpressing Oct4 also overexpress other CSC markers such as CD133, CD34, and ALDH1. Oct4 is also involved in the survival, self-renewal, metastasis, and drug resistance of CSCs [89,90,91,92]. These results indicate that PrPC directly regulates Oct4 expression, whereas it indirectly regulates Nanog, Sox2, and ALDH1A to promote the self-renewal and survival of CSCs [31].

In summary, Figure 1 shows the proteins and signaling pathways that seem to be affected by PrPC expression. The information on these interactions was retrieved from several studies that have been already mentioned in this review. Although PrPC appear to interact and activate several interaction partners and signaling pathways to promote tumor progression, it is difficult to say that this applies to all cancer cells. The role of PrPC in cancer needs to be interpreted differently depending on the cell type and interaction partner.

Figure 1.

Figure 1

Open in a new tab

Proteins and signaling pathways that seem to be affected by PrPC expression. Various proteins and signaling pathways reportedly interact with or are modulated by PrPC. Some of the proteins shown are known to be regulated indirectly through other proteins rather than direct interaction with PrPC. PrPC: prion protein, ECM: extracellular matrix, CSC: cancer stem cell.

7. Cancer Treatment by Targeting PrPC

Cancer growth can be inhibited by inhibiting the interaction between PrPC and other proteins. Lopes et al. used a peptide named HOP/STI1230–245 corresponding to the prion binding site of HOP to inhibit the interaction between PrPC and HOP [56]. Treatment with only the peptide did not inhibit cell proliferation, but co-treatment with HOP inhibited the interaction between HOP and PrPC and HOP-induced cell proliferation. In addition, HOP/STI1230–245 treatment of orthotopic xenografts inhibited tumor growth and improved animal survival while maintaining cognitive performance [56]. It should be noted that the blockage of PrPC and HOP may be deleterious, because long-term [93] but not short-term [94] intracranial infusion of antibodies against PrPC, particularly those against its globular domain, can be neurotoxic [93].

Recently, our group identified that HSP family A (Hsp 70) member 1-like, HSPA1L, regulates the expression of PrPC [77]. It was confirmed that the expression of HSPA1L increased in colon cancer cells and cancer tissues. We also demonstrated that HSPA1L increases the stability of HIF-1α by binding with HIF-1α and promotes the accumulation of PrPC. When HSPA1L expression was knocked down, HIF-1α stability and PrPC expression decreased [77]. In addition, we also showed that HSPA1L binds to GP78 and inhibits its ubiquitination activity, thereby reducing the ubiquitination of PrPC. Several studies have indicated that deregulation of several E3 ligases affects the growth and metastasis of cancer and the growth of CSCs [95,96,97,98]. GP78 is an ER membrane-anchored E3 ligase that regulates the progression of cancer cells through ubiquitin ligase activity. For example, downregulation of GP78-mediated ubiquitination is known to inhibit metastasis in breast cancer cells [99]. We hypothesized that HIF-1α and HSPA1L are major therapeutic targets for colorectal cancer. Indeed, knockdown of HIF-1α and HSPA1L using siRNAs inhibited cancer sphere formation in HT-29 and S707 cells. In an in vivo xenograft model, knockdown of HIF-1α or HSPA1L inhibited tumor growth and liver metastasis (Figure 2). In addition, when both genes were knocked down simultaneously, cancer growth and liver metastasis were further suppressed [77]. These results indicated that PrPC is important in tumor progression, and the suppression of PrPC expression by targeting HIF-1α and HSPA1L could be a promising therapeutic strategy to treat cancer.

Figure 2.

Figure 2

Open in a new tab

Strategies to suppress the tumor progression by regulating the expression and function of PrPC. (a) In tumor niche, the expression of HSPA1L is increased. HSPA1L binds and stabilizes HIF-1α. HSPA1L directly binds to GP78 and inhibits its ubiquitination activity. Overall, PrPC expression is increased in tumor cells. Therefore, knocking down HSPA1L and HIF-1α expression induces degradation of PrPC and tumor suppression. (b) Direct targeting of PrPC using anti-PrPC antibodies has been demonstrated as a potent cancer therapy. Anti-PrPC antibody also can be used as a combination therapy with conventional anticancer drugs.

Anti-prion antibodies can be utilized for the treatment of cancer. Antibody therapeutics have been used in the treatment of cancer, unlike existing anticancer drugs, as they have fewer side effects and exhibit high efficacy. For the development of effective antibody therapeutics, the discovery of specific molecular biomarkers in a wide range of solid malignancies is a key process [100]. The functions of PrPC in the growth, metastasis, drug resistance, and CSC properties of various types of cancer suggest that it is a promising therapeutic target for cancer treatment. We confirmed that an anti-prion antibody showed anticancer effects in a xenograft model and that superior therapeutic effects appeared when the conventional anticancer drugs and anti-prion antibody were applied in combination (unpublished data) (Figure 2). Furthermore, compared to cetuximab, an EGFR-targeting antibody, the anti-prion antibody showed similar anticancer effects with 10 times lower dose in the xenograft mouse model (unpublished data).

Similar to our data, a previous study has revealed the effective epitope of PrPC for antibody-mediated colon cancer therapy [101]. In colon cancer cell line HCT116 cells, epitope 139–142 and epitope 141–151 targeting anti-PrP antibodies highly inhibited the proliferative capacity of cells, compared with those of epitope 93–109 and epitope 101–112 [101]. Furthermore, epitope 141–151 targeting anti-PrP was approximately 10-fold more active than that of epitope 93–109 targeting anti-PrP [101]. These data indicate that effectiveness of anti-PrP antibodies might be related to the epitope-binding region. Further studies on anti-PrP structure and its targeting epitope site for cancer therapy are needed. One study has shown that N-terminal domain of PrPC is a direct binding and sequestering site on anti-tumor drug, doxorubicin, in breast cancer [67]. This study suggests that N-terminal-domain-targeting anti-PrP antibodies might be effective antibody therapy when combined with anti-tumor drugs, for cancer treatment.

Although antibody therapy is a promising cancer treatment, resistance may arise due to the characteristics of cancer cells, such as intrinsic phenotypic variation and adaptive phenotypic modifications [100,102,103,104,105]. Antibody-drug conjugates (ADCs), which are novel antibody-based therapeutics, are another option for treating tumors. ADC is a technology that focuses on targeting only cancer cells by exploiting the advantages of antibodies: specificity, non-toxicity in circulation, and pharmacokinetics. ADC is known to enter cells through clathrin-mediated endocytosis [106]. The endosome that harbors ADC binds to other vesicles in the cell and forms an endo-lysosome. A protease cleaves the linker of the ADC and activates free drugs to move into the cytoplasm. The drugs bind to the molecular target, causing apoptosis of the tumor cells. A representative example of a successful ADC is Trastuzumab Emtansine (T-DM1) [107,108,109]. T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer who were previously treated with trastuzumab and a taxane. Anti-prion antibodies, such as T-DM1, are expected to be developed as anticancer agents in the form of ADCs.

8. Conclusions

Several studies have suggested that PrPC promotes tumor progression. It has been demonstrated that PrPC is overexpressed in various types of cancer cells and tumor tissues, including gastric, pancreatic, breast, and colon cancers, as well as melanoma, GBM, and schwannoma. In addition, it has been shown that PrPC regulates cell proliferation, metastasis, drug resistance, and cancer stem cell properties through signaling pathways, such as PI3K-Akt and Notch, and interaction with ECM, cell surface molecules, and cancer stem cell markers. It should be noted that the function of PrPC in cancer should be interpreted depending on the cell type and the molecule that interacts with it. Nevertheless, further research is needed to elucidate the function of PrPC in tumor progression. However, there seems to be no disagreement that PrPC is a promising target for cancer treatment.

In addition to PrPC, the misfolded prion protein (PrPSc) may be highly expressed in cancer patients compared to the healthy people. Recently, somatic mutations in PRNP were analyzed in 10,967 cancer patients using the Cancer Genome atlas (TCGA) database [110]. A total of 48 mutations in PRNP gene were identified in cancer patient. Among them, eight somatic mutations— G131V, D167N, V180I, D202N, V203I, R208C, R208H, and E211Q—are known as pathogenic mutations of prion diseases. Interestingly, it has been reported that PrPSc was also detected in healthy people, who had not been diagnosed with prion diseases [111]. These results may indicate that cancer patients carrying pathogenic somatic mutations of PRNP may produce PrPSc and may not be diagnosed with prion disease.

In this review, we suggest that prion targeting is a promising strategy to treat cancer. Regulating the expression of HSPL1A and HIF-1α, which are involved in the stability and degradation of PrPC, effectively inhibits cancer growth and metastasis. In addition, an anti-prion antibody has been used to inhibit the growth of cancer. Nevertheless, further studies are needed to verify the anticancer effect and safety of prion targeting in various cancer models. To date, no clinical trials using prion targeting have been conducted; therefore, the effectiveness and safety of cancer treatment strategies using prion targeting should also be verified.

Acknowledgments

This work was supported by a grant from the National Research Foundation funded by the Korean government (2016R1D1A3B01007727). The funders had no role in the manuscript design, preparation of the manuscript, or decision to publish.

Author Contributions

G.G.: designed and drafted the manuscript; S.H.L.: drafted the manuscript, procured funding, and supervised the study. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by a National Research Foundation grant funded by the Korean government (2016R1D1A3B01007727).

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Prusiner S.B. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136–144. doi: 10.1126/science.6801762. [DOI] [PubMed] [Google Scholar]
  • 2.Caughey B., Chesebro B. Prion protein and the transmissible spongiform encephalopathies. Trends Cell Biol. 1997;7:56–62. doi: 10.1016/S0962-8924(96)10054-4. [DOI] [PubMed] [Google Scholar]
  • 3.Aguzzi A., Heppner F.L. Pathogenesis of prion diseases: A progress report. Cell Death Differ. 2000;7:889–902. doi: 10.1038/sj.cdd.4400737. [DOI] [PubMed] [Google Scholar]
  • 4.Castle A.R., Gill A.C. Physiological Functions of the Cellular Prion Protein. Front. Mol. Biosci. 2017;4:19. doi: 10.3389/fmolb.2017.00019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Dupiereux I., Falisse-Poirrier N., Zorzi W., Watt N.T., Thellin O., Zorzi D., Pierard O., Hooper N.M., Heinen E., Elmoualij B. Protective effect of prion protein via the N-terminal region in mediating a protective effect on paraquat-induced oxidative injury in neuronal cells. J. Neurosci. Res. 2008;86:653–659. doi: 10.1002/jnr.21506. [DOI] [PubMed] [Google Scholar]
  • 6.Graner E., Mercadante A.F., Zanata S.M., Martins V.R., Jay D.G., Brentani R.R. Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett. 2000;482:257–260. doi: 10.1016/S0014-5793(00)02070-6. [DOI] [PubMed] [Google Scholar]
  • 7.Ramljak S., Asif A.R., Armstrong V.W., Wrede A., Groschup M.H., Buschmann A., Schulz-Schaeffer W., Bodemer W., Zerr I. Physiological role of the cellular prion protein (PrPc): Protein profiling study in two cell culture systems. J. Proteome Res. 2008;7:2681–2695. doi: 10.1021/pr7007187. [DOI] [PubMed] [Google Scholar]
  • 8.Tobler I., Gaus S.E., Deboer T., Achermann P., Fischer M., Rulicke T., Moser M., Oesch B., McBride P.A., Manson J.C. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. 1996;380:639–642. doi: 10.1038/380639a0. [DOI] [PubMed] [Google Scholar]
  • 9.Bremer J., Baumann F., Tiberi C., Wessig C., Fischer H., Schwarz P., Steele A.D., Toyka K.V., Nave K.A., Weis J., et al. Axonal prion protein is required for peripheral myelin maintenance. Nat. Neurosci. 2010;13:310–318. doi: 10.1038/nn.2483. [DOI] [PubMed] [Google Scholar]
  • 10.Haddon D.J., Hughes M.R., Antignano F., Westaway D., Cashman N.R., McNagny K.M. Prion protein expression and release by mast cells after activation. J. Infect. Dis. 2009;200:827–831. doi: 10.1086/605022. [DOI] [PubMed] [Google Scholar]
  • 11.Santos T.G., Lopes M.H., Martins V.R. Targeting prion protein interactions in cancer. Prion. 2015;9:165–173. doi: 10.1080/19336896.2015.1027855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Gao Z., Peng M., Chen L., Yang X., Li H., Shi R., Wu G., Cai L., Song Q., Li C. Prion Protein Protects Cancer Cells against Endoplasmic Reticulum Stress Induced Apoptosis. Virol. Sin. 2019;34:222–234. doi: 10.1007/s12250-019-00107-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Dery M.A., Jodoin J., Ursini-Siegel J., Aleynikova O., Ferrario C., Hassan S., Basik M., LeBlanc A.C. Endoplasmic reticulum stress induces PRNP prion protein gene expression in breast cancer. Breast Cancer Res. 2013;15:R22. doi: 10.1186/bcr3398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Mehrpour M., Codogno P. Prion protein: From physiology to cancer biology. Cancer Lett. 2010;290:1–23. doi: 10.1016/j.canlet.2009.07.009. [DOI] [PubMed] [Google Scholar]
  • 15.Tang Z., Ma J., Zhang W., Gong C., He J., Wang Y., Yu G., Yuan C., Wang X., Sun Y., et al. The Role of Prion Protein Expression in Predicting Gastric Cancer Prognosis. J. Cancer. 2016;7:984–990. doi: 10.7150/jca.14237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Tanaka S., Maeda Y., Tashima Y., Kinoshita T. Inositol deacylation of glycosylphosphatidylinositol-anchored proteins is mediated by mammalian PGAP1 and yeast Bst1p. J. Biol. Chem. 2004;279:14256–14263. doi: 10.1074/jbc.M313755200. [DOI] [PubMed] [Google Scholar]
  • 17.Bonnon C., Wendeler M.W., Paccaud J.P., Hauri H.P. Selective export of human GPI-anchored proteins from the endoplasmic reticulum. J. Cell Sci. 2010;123:1705–1715. doi: 10.1242/jcs.062950. [DOI] [PubMed] [Google Scholar]
  • 18.Sarnataro D., Campana V., Paladino S., Stornaiuolo M., Nitsch L., Zurzolo C. PrP(C) association with lipid rafts in the early secretory pathway stabilizes its cellular conformation. Mol. Biol. Cell. 2004;15:4031–4042. doi: 10.1091/mbc.e03-05-0271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Campana V., Sarnataro D., Zurzolo C. The highways and byways of prion protein trafficking. Trends Cell Biol. 2005;15:102–111. doi: 10.1016/j.tcb.2004.12.002. [DOI] [PubMed] [Google Scholar]
  • 20.Shyng S.L., Huber M.T., Harris D.A. A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells. J. Biol. Chem. 1993;268:15922–15928. [PubMed] [Google Scholar]
  • 21.Sunyach C., Jen A., Deng J., Fitzgerald K.T., Frobert Y., Grassi J., McCaffrey M.W., Morris R. The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein. EMBO J. 2003;22:3591–3601. doi: 10.1093/emboj/cdg344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Magalhaes A.C., Silva J.A., Lee K.S., Martins V.R., Prado V.F., Ferguson S.S., Gomez M.V., Brentani R.R., Prado M.A. Endocytic intermediates involved with the intracellular trafficking of a fluorescent cellular prion protein. J. Biol. Chem. 2002;277:33311–33318. doi: 10.1074/jbc.M203661200. [DOI] [PubMed] [Google Scholar]
  • 23.Lee K.S., Magalhaes A.C., Zanata S.M., Brentani R.R., Martins V.R., Prado M.A. Internalization of mammalian fluorescent cellular prion protein and N-terminal deletion mutants in living cells. J. Neurochem. 2001;79:79–87. doi: 10.1046/j.1471-4159.2001.00529.x. [DOI] [PubMed] [Google Scholar]
  • 24.Gu Y., Hinnerwisch J., Fredricks R., Kalepu S., Mishra R.S., Singh N. Identification of cryptic nuclear localization signals in the prion protein. NeuroBiol. Dis. 2003;12:133–149. doi: 10.1016/S0969-9961(02)00014-1. [DOI] [PubMed] [Google Scholar]
  • 25.Morel E., Fouquet S., Strup-Perrot C., Pichol Thievend C., Petit C., Loew D., Faussat A.M., Yvernault L., Pincon-Raymond M., Chambaz J., et al. The cellular prion protein PrP(c) is involved in the proliferation of epithelial cells and in the distribution of junction-associated proteins. PLoS ONE. 2008;3:e3000. doi: 10.1371/annotation/0b364095-9f93-4cb9-9a2e-aae5ed1bf362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hachiya N.S., Yamada M., Watanabe K., Jozuka A., Ohkubo T., Sano K., Takeuchi Y., Kozuka Y., Sakasegawa Y., Kaneko K. Mitochondrial localization of cellular prion protein (PrPC) invokes neuronal apoptosis in aged transgenic mice overexpressing PrPC. Neurosci. Lett. 2005;374:98–103. doi: 10.1016/j.neulet.2004.10.044. [DOI] [PubMed] [Google Scholar]
  • 27.Satoh J., Onoue H., Arima K., Yamamura T. The 14-3-3 protein forms a molecular complex with heat shock protein Hsp60 and cellular prion protein. J. Neuropathol. Exp. Neurol. 2005;64:858–868. doi: 10.1097/01.jnen.0000182979.56612.08. [DOI] [PubMed] [Google Scholar]
  • 28.Han H., Bearss D.J., Browne L.W., Calaluce R., Nagle R.B., Von Hoff D.D. Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res. 2002;62:2890–2896. [PubMed] [Google Scholar]
  • 29.Zhao Y., You H., Liu F., An H., Shi Y., Yu Q., Fan D. Differentially expressed gene profiles between multidrug resistant gastric adenocarcinoma cells and their parental cells. Cancer Lett. 2002;185:211–218. doi: 10.1016/S0304-3835(02)00264-1. [DOI] [PubMed] [Google Scholar]
  • 30.Domingues P.H., Nanduri L.S.Y., Seget K., Venkateswaran S.V., Agorku D., Vigano C., von Schubert C., Nigg E.A., Swanton C., Sotillo R., et al. Cellular Prion Protein PrP(C) and Ecto-5′-Nucleotidase Are Markers of the Cellular Stress Response to Aneuploidy. Cancer Res. 2017;77:2914–2926. doi: 10.1158/0008-5472.CAN-16-3052. [DOI] [PubMed] [Google Scholar]
  • 31.Lee J.H., Yun C.W., Han Y.S., Kim S., Jeong D., Kwon H.Y., Kim H., Baek M.J., Lee S.H. Melatonin and 5-fluorouracil co-suppress colon cancer stem cells by regulating cellular prion protein-Oct4 axis. J. Pineal. Res. 2018;65:e12519. doi: 10.1111/jpi.12519. [DOI] [PubMed] [Google Scholar]
  • 32.Bounhar Y., Zhang Y., Goodyer C.G., LeBlanc A. Prion protein protects human neurons against Bax-mediated apoptosis. J. Biol. Chem. 2001;276:39145–39149. doi: 10.1074/jbc.C100443200. [DOI] [PubMed] [Google Scholar]
  • 33.Roucou X., Giannopoulos P.N., Zhang Y., Jodoin J., Goodyer C.G., LeBlanc A. Cellular prion protein inhibits proapoptotic Bax conformational change in human neurons and in breast carcinoma MCF-7 cells. Cell Death Differ. 2005;12:783–795. doi: 10.1038/sj.cdd.4401629. [DOI] [PubMed] [Google Scholar]
  • 34.Yu G., Jiang L., Xu Y., Guo H., Liu H., Zhang Y., Yang H., Yuan C., Ma J. Silencing prion protein in MDA-MB-435 breast cancer cells leads to pleiotropic cellular responses to cytotoxic stimuli. PLoS ONE. 2012;7:e48146. doi: 10.1371/journal.pone.0048146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Lopes M.H., Hajj G.N., Muras A.G., Mancini G.L., Castro R.M., Ribeiro K.C., Brentani R.R., Linden R., Martins V.R. Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J. Neurosci. 2005;25:11330–11339. doi: 10.1523/JNEUROSCI.2313-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Beraldo F.H., Arantes C.P., Santos T.G., Queiroz N.G., Young K., Rylett R.J., Markus R.P., Prado M.A., Martins V.R. Role of alpha7 nicotinic acetylcholine receptor in calcium signaling induced by prion protein interaction with stress-inducible protein 1. J. Biol. Chem. 2010;285:36542–36550. doi: 10.1074/jbc.M110.157263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ostapchenko V.G., Beraldo F.H., Mohammad A.H., Xie Y.F., Hirata P.H., Magalhaes A.C., Lamour G., Li H., Maciejewski A., Belrose J.C., et al. The prion protein ligand, stress-inducible phosphoprotein 1, regulates amyloid-beta oligomer toxicity. J. Neurosci. 2013;33:16552–16564. doi: 10.1523/JNEUROSCI.3214-13.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Rachidi W., Vilette D., Guiraud P., Arlotto M., Riondel J., Laude H., Lehmann S., Favier A. Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery. J. Biol. Chem. 2003;278:9064–9072. doi: 10.1074/jbc.M211830200. [DOI] [PubMed] [Google Scholar]
  • 39.Zeng F., Watt N.T., Walmsley A.R., Hooper N.M. Tethering the N-terminus of the prion protein compromises the cellular response to oxidative stress. J. Neurochem. 2003;84:480–490. doi: 10.1046/j.1471-4159.2003.01529.x. [DOI] [PubMed] [Google Scholar]
  • 40.Brown D.R., Nicholas R.S., Canevari L. Lack of prion protein expression results in a neuronal phenotype sensitive to stress. J. Neurosci. Res. 2002;67:211–224. doi: 10.1002/jnr.10118. [DOI] [PubMed] [Google Scholar]
  • 41.Anantharam V., Kanthasamy A., Choi C.J., Martin D.P., Latchoumycandane C., Richt J.A., Kanthasamy A.G. Opposing roles of prion protein in oxidative stress- and ER stress-induced apoptotic signaling. Free Radic. Biol. Med. 2008;45:1530–1541. doi: 10.1016/j.freeradbiomed.2008.08.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Santuccione A., Sytnyk V., Leshchyns’ka I., Schachner M. Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J. Cell Biol. 2005;169:341–354. doi: 10.1083/jcb.200409127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Llorens F., Carulla P., Villa A., Torres J.M., Fortes P., Ferrer I., del Rio J.A. PrP(C) regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells. J. Neurochem. 2013;127:124–138. doi: 10.1111/jnc.12283. [DOI] [PubMed] [Google Scholar]
  • 44.Loubet D., Dakowski C., Pietri M., Pradines E., Bernard S., Callebert J., Ardila-Osorio H., Mouillet-Richard S., Launay J.M., Kellermann O., et al. Neuritogenesis: The prion protein controls beta1 integrin signaling activity. FASEB J. 2012;26:678–690. doi: 10.1096/fj.11-185579. [DOI] [PubMed] [Google Scholar]
  • 45.Graner E., Mercadante A.F., Zanata S.M., Forlenza O.V., Cabral A.L., Veiga S.S., Juliano M.A., Roesler R., Walz R., Minetti A., et al. Cellular prion protein binds laminin and mediates neuritogenesis. Brain Res. Mol. Brain Res. 2000;76:85–92. doi: 10.1016/S0169-328X(99)00334-4. [DOI] [PubMed] [Google Scholar]
  • 46.Caetano F.A., Lopes M.H., Hajj G.N., Machado C.F., Pinto Arantes C., Magalhaes A.C., Vieira Mde P., Americo T.A., Massensini A.R., Priola S.A., et al. Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1. J. Neurosci. 2008;28:6691–6702. doi: 10.1523/JNEUROSCI.1701-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Lee Y.J., Baskakov I.V. The cellular form of the prion protein guides the differentiation of human embryonic stem cells into neuron-, oligodendrocyte-, and astrocyte-committed lineages. Prion. 2014;8:266–275. doi: 10.4161/pri.32079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Steele A.D., Emsley J.G., Ozdinler P.H., Lindquist S., Macklis J.D. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc. Natl. Acad. Sci. USA. 2006;103:3416–3421. doi: 10.1073/pnas.0511290103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Miele G., Jeffrey M., Turnbull D., Manson J., Clinton M. Ablation of cellular prion protein expression affects mitochondrial numbers and morphology. Biochem. Biophys. Res. Commun. 2002;291:372–377. doi: 10.1006/bbrc.2002.6460. [DOI] [PubMed] [Google Scholar]
  • 50.Stella R., Cifani P., Peggion C., Hansson K., Lazzari C., Bendz M., Levander F., Sorgato M.C., Bertoli A., James P. Relative quantification of membrane proteins in wild-type and prion protein (PrP)-knockout cerebellar granule neurons. J. Proteome Res. 2012;11:523–536. doi: 10.1021/pr200759m. [DOI] [PubMed] [Google Scholar]
  • 51.Liang J., Luo G., Ning X., Shi Y., Zhai H., Sun S., Jin H., Liu Z., Zhang F., Lu Y., et al. Differential expression of calcium-related genes in gastric cancer cells transfected with cellular prion protein. Biochem. Cell Biol. 2007;85:375–383. doi: 10.1139/O07-052. [DOI] [PubMed] [Google Scholar]
  • 52.Li Q.Q., Cao X.X., Xu J.D., Chen Q., Wang W.J., Tang F., Chen Z.Q., Liu X.P., Xu Z.D. The role of P-glycoprotein/cellular prion protein interaction in multidrug-resistant breast cancer cells treated with paclitaxel. Cell Mol. Life Sci. 2009;66:504–515. doi: 10.1007/s00018-008-8548-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Le Corre D., Ghazi A., Balogoun R., Pilati C., Aparicio T., Martin-Lanneree S., Marisa L., Djouadi F., Poindessous V., Crozet C., et al. The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancer. EBioMedicine. 2019;46:94–104. doi: 10.1016/j.ebiom.2019.07.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Li Q.Q., Sun Y.P., Ruan C.P., Xu X.Y., Ge J.H., He J., Xu Z.D., Wang Q., Gao W.C. Cellular prion protein promotes glucose uptake through the Fyn-HIF-2alpha-Glut1 pathway to support colorectal cancer cell survival. Cancer Sci. 2011;102:400–406. doi: 10.1111/j.1349-7006.2010.01811.x. [DOI] [PubMed] [Google Scholar]
  • 55.Chieng C.K., Say Y.H. Cellular prion protein contributes to LS 174T colon cancer cell carcinogenesis by increasing invasiveness and resistance against doxorubicin-induced apoptosis. Tumour. Biol. 2015;36:8107–8120. doi: 10.1007/s13277-015-3530-z. [DOI] [PubMed] [Google Scholar]
  • 56.Lopes M.H., Santos T.G., Rodrigues B.R., Queiroz-Hazarbassanov N., Cunha I.W., Wasilewska-Sampaio A.P., Costa-Silva B., Marchi F.A., Bleggi-Torres L.F., Sanematsu P.I., et al. Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene. 2015;34:3305–3314. doi: 10.1038/onc.2014.261. [DOI] [PubMed] [Google Scholar]
  • 57.Corsaro A., Bajetto A., Thellung S., Begani G., Villa V., Nizzari M., Pattarozzi A., Solari A., Gatti M., Pagano A., et al. Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells. Oncotarget. 2016;7:38638–38657. doi: 10.18632/oncotarget.9575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Provenzano L., Ryan Y., Hilton D.A., Lyons-Rimmer J., Dave F., Maze E.A., Adams C.L., Rigby-Jones R., Ammoun S., Hanemann C.O. Cellular prion protein (PrP(C)) in the development of Merlin-deficient tumours. Oncogene. 2017;36:6132–6142. doi: 10.1038/onc.2017.200. [DOI] [PubMed] [Google Scholar]
  • 59.Liang J., Ge F., Guo C., Luo G., Wang X., Han G., Zhang D., Wang J., Li K., Pan Y., et al. Inhibition of PI3K/Akt partially leads to the inhibition of PrP(C)-induced drug resistance in gastric cancer cells. FEBS J. 2009;276:685–694. doi: 10.1111/j.1742-4658.2008.06816.x. [DOI] [PubMed] [Google Scholar]
  • 60.Liang J., Wang J., Luo G., Pan Y., Wang X., Guo C., Zhang D., Yin F., Zhang X., Liu J., et al. Function of PrPC (1-OPRD) in biological activities of gastric cancer cell lines. J. Cell Mol. Med. 2009;13:4453–4464. doi: 10.1111/j.1582-4934.2009.00687.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Li C., Xin W., Sy M.S. Binding of pro-prion to filamin A: By design or an unfortunate blunder. Oncogene. 2010;29:5329–5345. doi: 10.1038/onc.2010.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Wang Y., Yu S., Huang D., Cui M., Hu H., Zhang L., Wang W., Parameswaran N., Jackson M., Osborne B., et al. Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1. Am. J. Pathol. 2016;186:2945–2956. doi: 10.1016/j.ajpath.2016.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Pan Y., Zhao L., Liang J., Liu J., Shi Y., Liu N., Zhang G., Jin H., Gao J., Xie H., et al. Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB J. 2006;20:1886–1888. doi: 10.1096/fj.06-6138fje. [DOI] [PubMed] [Google Scholar]
  • 64.De Lacerda T.C., Costa-Silva B., Giudice F.S., Dias M.V., de Oliveira G.P., Teixeira B.L., Dos Santos T.G., Martins V.R. Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells. Clin. Exp. Metastasis. 2016;33:441–451. doi: 10.1007/s10585-016-9788-8. [DOI] [PubMed] [Google Scholar]
  • 65.Li C., Yu S., Nakamura F., Pentikainen O.T., Singh N., Yin S., Xin W., Sy M.S. Pro-prion binds filamin A, facilitating its interaction with integrin beta1, and contributes to melanomagenesis. J. Biol. Chem. 2010;285:30328–30339. doi: 10.1074/jbc.M110.147413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Yang L., Gao Z., Hu L., Wu G., Yang X., Zhang L., Zhu Y., Wong B.S., Xin W., Sy M.S., et al. Glycosylphosphatidylinositol anchor modification machinery deficiency is responsible for the formation of pro-prion protein (PrP) in BxPC-3 cells and increases cancer cell motility. J. Biol. Chem. 2016;291:6785. doi: 10.1074/jbc.A115.705830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Du L., Rao G., Wang H., Li B., Tian W., Cui J., He L., Laffin B., Tian X., Hao C., et al. CD44-positive cancer stem cells expressing cellular prion protein contribute to metastatic capacity in colorectal cancer. Cancer Res. 2013;73:2682–2694. doi: 10.1158/0008-5472.CAN-12-3759. [DOI] [PubMed] [Google Scholar]
  • 68.Lu W., Kang Y. Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis. Dev. Cell. 2019;49:361–374. doi: 10.1016/j.devcel.2019.04.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Meslin F., Hamai A., Gao P., Jalil A., Cahuzac N., Chouaib S., Mehrpour M. Silencing of prion protein sensitizes breast adriamycin-resistant carcinoma cells to TRAIL-mediated cell death. Cancer Res. 2007;67:10910–10919. doi: 10.1158/0008-5472.CAN-07-0512. [DOI] [PubMed] [Google Scholar]
  • 70.Meslin F., Conforti R., Mazouni C., Morel N., Tomasic G., Drusch F., Yacoub M., Sabourin J.C., Grassi J., Delaloge S., et al. Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer. Ann. Oncol. 2007;18:1793–1798. doi: 10.1093/annonc/mdm406. [DOI] [PubMed] [Google Scholar]
  • 71.Park J.Y., Jeong J.K., Lee J.H., Moon J.H., Kim S.W., Lee Y.J., Park S.Y. Induction of cellular prion protein (PrPc) under hypoxia inhibits apoptosis caused by TRAIL treatment. Oncotarget. 2015;6:5342–5353. doi: 10.18632/oncotarget.3028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Vassallo N., Herms J., Behrens C., Krebs B., Saeki K., Onodera T., Windl O., Kretzschmar H.A. Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival. Biochem. Biophys. Res. Commun. 2005;332:75–82. doi: 10.1016/j.bbrc.2005.04.099. [DOI] [PubMed] [Google Scholar]
  • 73.Weise J., Sandau R., Schwarting S., Crome O., Wrede A., Schulz-Schaeffer W., Zerr I., Bahr M. Deletion of cellular prion protein results in reduced Akt activation, enhanced postischemic caspase-3 activation, and exacerbation of ischemic brain injury. Stroke. 2006;37:1296–1300. doi: 10.1161/01.STR.0000217262.03192.d4. [DOI] [PubMed] [Google Scholar]
  • 74.Lee J.H., Yun C.W., Lee S.H. Cellular Prion Protein Enhances Drug Resistance of Colorectal Cancer Cells via Regulation of a Survival Signal Pathway. Biomol. Ther. (Seoul) 2018;26:313–321. doi: 10.4062/biomolther.2017.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Lee J.H., Yoon Y.M., Han Y.S., Yun C.W., Lee S.H. Melatonin Promotes Apoptosis of Oxaliplatin-resistant Colorectal Cancer Cells Through Inhibition of Cellular Prion Protein. Anticancer Res. 2018;38:1993–2000. doi: 10.21873/anticanres.12437. [DOI] [PubMed] [Google Scholar]
  • 76.Go G., Yun C.W., Yoon Y.M., Lim J.H., Lee J.H., Lee S.H. Role of PrP(C) in Cancer Stem Cell Characteristics and Drug Resistance in Colon Cancer Cells. Anticancer Res. 2020;40:5611–5620. doi: 10.21873/anticanres.14574. [DOI] [PubMed] [Google Scholar]
  • 77.Lee J.H., Han Y.S., Yoon Y.M., Yun C.W., Yun S.P., Kim S.M., Kwon H.Y., Jeong D., Baek M.J., Lee H.J., et al. Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1alpha/GP78 axis. Oncogene. 2017;36:6555–6567. doi: 10.1038/onc.2017.263. [DOI] [PubMed] [Google Scholar]
  • 78.Al-Hajj M., Clarke M.F. Self-renewal and solid tumor stem cells. Oncogene. 2004;23:7274–7282. doi: 10.1038/sj.onc.1207947. [DOI] [PubMed] [Google Scholar]
  • 79.Beck B., Blanpain C. Unravelling cancer stem cell potential. Nat. Rev. Cancer. 2013;13:727–738. doi: 10.1038/nrc3597. [DOI] [PubMed] [Google Scholar]
  • 80.Ho M.M., Ng A.V., Lam S., Hung J.Y. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007;67:4827–4833. doi: 10.1158/0008-5472.CAN-06-3557. [DOI] [PubMed] [Google Scholar]
  • 81.Tehranchi R., Woll P.S., Anderson K., Buza-Vidas N., Mizukami T., Mead A.J., Astrand-Grundstrom I., Strombeck B., Horvat A., Ferry H., et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N. Engl. J. Med. 2010;363:1025–1037. doi: 10.1056/NEJMoa0912228. [DOI] [PubMed] [Google Scholar]
  • 82.Dean M., Fojo T., Bates S. Tumour stem cells and drug resistance. Nat. Rev. Cancer. 2005;5:275–284. doi: 10.1038/nrc1590. [DOI] [PubMed] [Google Scholar]
  • 83.Wang Q., Qian J., Wang F., Ma Z. Cellular prion protein accelerates colorectal cancer metastasis via the Fyn-SP1-SATB1 axis. Oncol. Rep. 2012;28:2029–2034. doi: 10.3892/or.2012.2025. [DOI] [PubMed] [Google Scholar]
  • 84.Shibue T., Weinberg R.A. EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017;14:611–629. doi: 10.1038/nrclinonc.2017.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Cheng Y., Tao L., Xu J., Li Q., Yu J., Jin Y., Chen Q., Xu Z., Zou Q., Liu X. CD44/cellular prion protein interact in multidrug resistant breast cancer cells and correlate with responses to neoadjuvant chemotherapy in breast cancer patients. Mol. Carcinog. 2014;53:686–697. doi: 10.1002/mc.22021. [DOI] [PubMed] [Google Scholar]
  • 86.Iglesia R.P., Prado M.B., Cruz L., Martins V.R., Santos T.G., Lopes M.H. Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells. Stem Cell Res. Ther. 2017;8:76. doi: 10.1186/s13287-017-0518-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Kreso A., Dick J.E. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–291. doi: 10.1016/j.stem.2014.02.006. [DOI] [PubMed] [Google Scholar]
  • 88.Kim R.J., Nam J.S. OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer. Lab. Anim. Res. 2011;27:147–152. doi: 10.5625/lar.2011.27.2.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Yin X., Zhang B.H., Zheng S.S., Gao D.M., Qiu S.J., Wu W.Z., Ren Z.G. Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling. J. Hematol. Oncol. 2015;8:23. doi: 10.1186/s13045-015-0119-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Wang Y.J., Herlyn M. The emerging roles of Oct4 in tumor-initiating cells. Am. J. Physiol. Cell Physiol. 2015;309:C709–C718. doi: 10.1152/ajpcell.00212.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Lin Y., Yang Y., Li W., Chen Q., Li J., Pan X., Zhou L., Liu C., Chen C., He J., et al. Reciprocal regulation of Akt and Oct4 promotes the self-renewal and survival of embryonal carcinoma cells. Mol. Cell. 2012;48:627–640. doi: 10.1016/j.molcel.2012.08.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Wang X.Q., Ongkeko W.M., Chen L., Yang Z.F., Lu P., Chen K.K., Lopez J.P., Poon R.T., Fan S.T. Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology. 2010;52:528–539. doi: 10.1002/hep.23692. [DOI] [PubMed] [Google Scholar]
  • 93.Sonati T., Reimann R.R., Falsig J., Baral P.K., O’Connor T., Hornemann S., Yaganoglu S., Li B., Herrmann U.S., Wieland B., et al. The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein. Nature. 2013;501:102–106. doi: 10.1038/nature12402. [DOI] [PubMed] [Google Scholar]
  • 94.Coitinho A.S., Lopes M.H., Hajj G.N., Rossato J.I., Freitas A.R., Castro C.C., Cammarota M., Brentani R.R., Izquierdo I., Martins V.R. Short-term memory formation and long-term memory consolidation are enhanced by cellular prion association to stress-inducible protein 1. NeuroBiol. Dis. 2007;26:282–290. doi: 10.1016/j.nbd.2007.01.005. [DOI] [PubMed] [Google Scholar]
  • 95.Jones M.F., Hara T., Francis P., Li X.L., Bilke S., Zhu Y., Pineda M., Subramanian M., Bodmer W.F., Lal A. The CDX1-microRNA-215 axis regulates colorectal cancer stem cell differentiation. Proc. Natl. Acad. Sci. USA. 2015;112:E1550–E1558. doi: 10.1073/pnas.1503370112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Li N., Lorenzi F., Kalakouti E., Normatova M., Babaei-Jadidi R., Tomlinson I., Nateri A.S. FBXW7-mutated colorectal cancer cells exhibit aberrant expression of phosphorylated-p53 at Serine-15. Oncotarget. 2015;6:9240–9256. doi: 10.18632/oncotarget.3284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Zhang T., Kho D.H., Wang Y., Harazono Y., Nakajima K., Xie Y., Raz A. Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. PLoS ONE. 2015;10:e0118448. doi: 10.1371/journal.pone.0118448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Tsai Y.C., Mendoza A., Mariano J.M., Zhou M., Kostova Z., Chen B., Veenstra T., Hewitt S.M., Helman L.J., Khanna C., et al. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat. Med. 2007;13:1504–1509. doi: 10.1038/nm1686. [DOI] [PubMed] [Google Scholar]
  • 99.Chang Y.W., Tseng C.F., Wang M.Y., Chang W.C., Lee C.C., Chen L.T., Hung M.C., Su J.L. Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer. Oncogene. 2016;35:1517–1528. doi: 10.1038/onc.2015.214. [DOI] [PubMed] [Google Scholar]
  • 100.Cruz E., Kayser V. Monoclonal antibody therapy of solid tumors: Clinical limitations and novel strategies to enhance treatment efficacy. Biologics. 2019;13:33–51. doi: 10.2147/BTT.S166310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.McEwan J.F., Windsor M.L., Cullis-Hill S.D. Antibodies to prion protein inhibit human colon cancer cell growth. Tumour. Biol. 2009;30:141–147. doi: 10.1159/000225243. [DOI] [PubMed] [Google Scholar]
  • 102.Slamon D.J., Leyland-Jones B., Shak S., Fuchs H., Paton V., Bajamonde A., Fleming T., Eiermann W., Wolter J., Pegram M., et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101. [DOI] [PubMed] [Google Scholar]
  • 103.Graham J., Muhsin M., Kirkpatrick P. Cetuximab. Nat. Rev. Drug Discov. 2004;3:549–550. doi: 10.1038/nrd1445. [DOI] [PubMed] [Google Scholar]
  • 104.Reslan L., Dalle S., Dumontet C. Understanding and circumventing resistance to anticancer monoclonal antibodies. MAbs. 2009;1:222–229. doi: 10.4161/mabs.1.3.8292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Viloria-Petit A., Crombet T., Jothy S., Hicklin D., Bohlen P., Schlaeppi J.M., Rak J., Kerbel R.S. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res. 2001;61:5090–5101. [PubMed] [Google Scholar]
  • 106.Sutherland M.S., Sanderson R.J., Gordon K.A., Andreyka J., Cerveny C.G., Yu C., Lewis T.S., Meyer D.L., Zabinski R.F., Doronina S.O., et al. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J. Biol. Chem. 2006;281:10540–10547. doi: 10.1074/jbc.M510026200. [DOI] [PubMed] [Google Scholar]
  • 107.Verma S., Miles D., Gianni L., Krop I.E., Welslau M., Baselga J., Pegram M., Oh D.Y., Dieras V., Guardino E., et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012;367:1783–1791. doi: 10.1056/NEJMoa1209124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Hardy-Werbin M., Quiroga V., Cirauqui B., Romeo M., Felip E., Teruel I., Garcia J.J., Erasun C., Espana S., Cucurull M., et al. Real-world data on T-DM1 efficacy - results of a single-center retrospective study of HER2-positive breast cancer patients. Sci. Rep. 2019;9:12760. doi: 10.1038/s41598-019-49251-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Von Minckwitz G., Huang C.S., Mano M.S., Loibl S., Mamounas E.P., Untch M., Wolmark N., Rastogi P., Schneeweiss A., Redondo A., et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N. Engl. J. Med. 2019;380:617–628. doi: 10.1056/NEJMoa1814017. [DOI] [PubMed] [Google Scholar]
  • 110.Kim Y.C., Won S.Y., Jeong B.H. Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients. Cells. 2020;9:1480. doi: 10.3390/cells9061480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Gill O.N., Spencer Y., Richard-Loendt A., Kelly C., Brown D., Sinka K., Andrews N., Dabaghian R., Simmons M., Edwards P., et al. Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic. Acta Neuropathol. 2020;139:965–976. doi: 10.1007/s00401-020-02153-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES