Table 1. Classification of PR and PS gene sets in a series of pathways identified through Enrichr.
| Annotation terms | The importance of pathways in cancer and chemotherapy-related events | |
|---|---|---|
| KEGG | ||
| 1 | Transcriptional misregulation in cancer | Misregulation of a large amount of transcription factors, cofactors, and chromatin regulators, which direct gene expression programs, can cause various cancers [29, 30]. |
| 2 | Wnt SP | Wnt SP is implicated in a variety of cancers [31–33]. There is an interaction between Notch, Akt, TGF-β, Wnt, and HIF SPs found in this study [32, 34]. |
| 3 | SPs regulating pluripotency of stem cells | Wnt SP is necessary for the maintenance of cancer stem cells [35]. The key role of Wnt/β-catenin SP in regulating the differentiation of stem cell populations and the relationship between its dysregulation and numerous tumor types make this pathway an interesting target for anticancer therapeutics [36]. |
| 4 | Calcium SP | Several Ca+2-mediated SPs are dysregulated in tumor development and progression [37]. Doxorubicin increases the intracellular Ca+2 level [38–40]. Rituximab-induced translocation of CD20 to lipid rafts is important in increased intracellular Ca+2 levels, and downstream apoptotic signaling, [41] and Cardiotoxicity*[38, 39]. |
| 5 | Glioma | Secondary glioma may occur in patients due to therapy for a primary malignancy [42]. |
| 6 | Fc epsilon rI (FcεRI) SP | Infiltrating mast cells induce chemotherapy resistance through activating p38/p53/p21 in cancer cells [43]. The stem cell factor enhances mast cell degranulation and cytokine production through cross-linking of FcεRI. Mast cell activation results in the secretion of histamine, serotonin, tumor necrosis factor, kinins, and proteases stored in secretory granules [44]. |
| WikiPathways | ||
| 1 | IL-6 SP | In the hematopoietic system, the growth-regulatory role of IL-6 is often detected in tumors, which arise from the B cell compartment [45]. |
| 2 | Sphingolipid metabolism | De novo synthesis and hydrolysis of sphingomyelin are often involved in ceramide generation in response to cancer therapy. Dysregulated generation of ceramide and consumption of free ceramide by incorporation into sphingomyelin (or by deacylation of ceramide to form sphingosine) are associated with defects in therapy-induced apoptosis and chemoresistance. There are several classes of cytotoxic chemotherapeutics including vincristine, doxorubicin, and topoisomerase inhibitors (irinotecan and etoposide), which can lead to ceramide accumulation [46–48]. |
| Reactome | ||
| 1 | Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane | Although purine nucleosides are used exclusively against hematological malignancies, pyrimidine analogs typically show efficacy against solid tumors, as well [49]. Purine nucleoside analogs, such as fludarabine, cladribine, and clofarabine are substrates for SLC29A1, SLC29A2, SLC28A3, and SLC28A2 [49]. In contrast, pyrimidine analogs, such as gemcitabine, cytarabine, and azacytidine, are transported by SLC28A1 in addition to SLC29A1, SLC29A2, and SLC28A3 [49]. |
| 2 | Signaling by TGF-β receptor complex | Phosphorylation of Smad1 in TGF-β SP has been reported in NHL [50]. TGF-β contributes to both early suppression of malignancy and tumor progression in later stages [51–53]. TGF-β and Wnt SPs can synergistically promote tumorigenesis [34]. |
| 3 | CREB phosphorylation through the activation of CaMKII and Ras | CaMKII is expressed at high levels in some cancers [54]. Ras/MEK/ERK SP acts as a critical pathway in cancer development and resistance to chemotherapy [55, 56]. |
| 4 | Ras activation upon Ca2+ influx through NMDA receptor | Oncogenic mutations in a number of upstream or downstream components of Ras SP have been detected in a variety of cancers [57]. |
| Post NMDA receptor activation events | NMDA receptors are overexpressed in several cancers and play important roles in proliferation of cancer cells [58]. Overactivity of NMDA receptors is correlated to apoptotic neuronal damage [59]. One of the adverse effects of doxorubicin on normal cells is neurotoxicity due to the induction of apoptosis in neural cells§ [60, 61]. | |
| 6 | Gamma-carboxylation of protein precursors | Venous thromboembolism (VTE) is a frequent and potentially fatal complication associated with hematological and solid tumor malignancies. In patients with cancer, the occurrence of VTE is an indicator of poor prognosis. The annual incidence of VTE in patients on chemotherapy is estimated at 11%, which can rise to 20% or higher, depending on the type of drug(s) being used [62]. |
| 7 | VEGFR, FGFRs, and ERBB4 | The increased level of growth factors and their receptors (eg, VEGFR, FGFRs, and ERBB4) is associated with tumor formation and drug resistance [63–66]. |
| 8 | IFNγ signaling | Doxorubicin induces IFN-responsive genes via IFNγ-JAK-STAT1 SP, leading to doxorubicin cytotoxicity [67]. The cellular response to DNA damage is activation of IFN signaling [67]. |
| BioCarta | ||
| 1 | CXCR4 SP | The function of CXCL12/CXCR4 is essential for homing and/or engraftment of hematopoietic stem cells (HSCs) to the bone marrow after transplantation. Treatment of NHL patients with plerixafor (an antagonist of alpha CXCR4) and G-CSF caused an increase in the number of HSCs used for autologous transplantation [68]. |
| Panther | ||
| 1 | Metabotropic glutamate receptor group I and III pathways | mGlu receptors are as novel targets for the treatment of aggressive or chemotherapy-resistant tumors [69]. Tumors secreting glutamate are highly resistant to chemotherapy and standard apoptosis-inducing therapeutics [70]. |
| 2 | Oxytocin receptor mediated SP | Oxytocin receptor is in the cluster of overexpressed genes related to doxorubicin resistance [71]. |
| 3 | 5HT-2 type receptor mediated SP | Dysregulation of central 5HT metabolism or function may be a contributing factor in chemotherapy-induced nausea and vomiting, and cancer-related fatigue [72–74]. |
| 4 | Histamine H1 receptor mediated SP | Mast cell activation results in histamine release and diverse side effects [75]. High amounts of histamine as well as histamine receptors have been observed in different cancers [76]. A dose of doxorubicin (1 mg/kg) can lead to histamine and catecholamines release, producing the cardiomyopathy in dogs [77]. |
The effects of PR- and PS-related pathways in different cancers and chemoresistance are presented based on the KEGG, WikiPathways, Reactome, BioCarta, and Panther databases (white rows, PR; red rows, PS; and yellow rows, calcium SP as a common pathway between the groups). P-value less than 0.05 was considered statistically significant.
*Myofibrillar deterioration and intracellular calcium dysregulation are important mechanisms commonly associated with doxorubicin-induced cardiac toxicity. Doxorubicin-induced cardiotoxicity is also accompanied by an increase in the intracellular calcium levels.
§Glucocorticoids exert a significant protection against NMDA-induced neuronal necrosis, at least in part via their ability to enhance glutamine synthetase in glial cells.
Abbreviations:
BDNF: Brain-derived neurotrophic factor, CaMKII: Ca2+/calmodulin-dependent protein kinase II, ERBB4: Receptor tyrosine-protein kinase erbB-4, FGFRs: Fibroblast growth factor receptors, mGlu receptors: metabotropic glutamate receptors, NGF: Nerve growth factor, NMDAR: N-methyl-D-aspartate receptor, SP: Signaling pathway, and VEGFR: Vascular endothelial growth factor.