Table 1.
cAMP/PKA functions and POPDC proteins’ roles, downstream targets, and downregulations associated with various cancer types.
| Type of Cancer | cAMP/PKA Functions | Popeye Domain Containing Protein (POPDC) Cancer Types | Mechanisms and Roles of POPDC Proteins | POPDC Downstream Targets in Cancer Signaling Pathways and Protein Interactions |
|---|---|---|---|---|
| Squamous cell carcinoma ↑ | Increasing the invasion and metastasis in the esophagus by PKA phosphorylating vasodilator-stimulated-phosphoprotein (VASP) [49]. | POPDC1 in CRC, PC, BC, NSCLC, glioma, HNSCC, GC | Promoter hypermethylation [191,192,193,194] | POPDC1/ZO-1 protein interaction in trabecular meshwork cells, HCE, uveal melanoma prevents ZONAB-induced entry to cell cycle and translation of proliferative genes [195]. |
| Lymphoblastic leukemia ↓ | Autophagy, aided by cAMP-induced poly [ADP-ribose] polymerase 1 (PARP1) activation, may treat acute lymphoblastic leukemia [52]. | POPDC1 in HCC | Underexpression of miRNA-122 [188] and overexpression of netrin-1 [189]. | Occludin in HCE and uveal melanoma maintains tight junction formation [182,195]. |
| Liver cancer | PKA phosphorylates many substrates, including CIP4, facilitating HCC invasion and metastasis [58]. | POPDC2 in ductal breast carcinoma (especially HER2+ subtype) | Overexpressed at all clinical stages. Possibly implicated in cancer initiation and sustenance [190]. | LRP6 (Wnt/βcatenin pathway) in HEK293 cells, human colonoids, murine adenoma tumoroids prevents β-catenin activation by inhibition of LRP6 [196]. |
| The vasoactive intestinal peptide lowered cAMP levels, CREB expression, and phospho-CREB (Ser133) phosphorylation via inhibiting B-cell lymphoma-extra-large (Bcl-Xl) expression [59]. | POPDC3 in ductal breast carcinoma (especially HER2+ subtype) | Overexpressed at early clinical stages [190]. | PR61α (c-Myc pathway) in murine colitis-associated cancer cells promotes c-Myc ubiquitination/ degradation [193]. | |
| The catalytic subunit of PKA C (DNAJB1-protein kinase cAMP-activated catalytic subunit alpha (PRKACA)) was overexpressed, PKA activity increased [61]. | POPDC3 in head and neck squamous cell carcinoma (HNSCC) | Overexpression correlates with low patient survival. Potential biomarker for radiotherapy resistance [197]. | ||
| Prostate cancer | The high PKA expression promotes cell proliferation and carcinogenesis [71]. | POPDC3 in gastric cancer | Underexpression due to promoter hypermethylation. Lower POPDC3 levels correlate with increased depth of invasion and metastasis [192]. | |
| cAMP–PKA signaling pathway is required for high levels of osteocalcin and ostesialin production in androgen-independent prostate cancer [90]. | POPDC3 in esophageal and lung cancer | Overexpression of POPDC3 correlates with greater radiotherapy resistance [197]. | ||
| PKA activity may increase with depressive and behavioral stress [92,93]. | LRP6 (Wnt/βcatenin pathway) interacting with POPDC1 in HEK293 cells, human colonoids, murine adenoma tumoroids | Prevention of β-catenin activation by inhibition of LRP6 [196]. | ||
| Small-cell lung cancer (SCLC) ↓ | Inhibition of PKA activity [73]. | Occludin interacting with POPDC1 in HCE, uveal melanoma | Maintenance of tight junction formation [182,195]. | |
| Brain cancer | Stimulation of the cAMP pathway via PKA RII induces cell differentiation and death [74]. | |||
| The catalytic subunit of PKA was found to be decreased in high-grade gliomas [76]. | ||||
| Increased cAMP levels reduce phosphatidylinositol 3-kinase, which decreases neuroblastoma [77]. | ||||
| Lower AC and cAMP levels in glioblastoma cells [79]. |
Note: Promoter hypermethylation, underexpression of miRNA-122, which inhibits POPDC1 gene transcription, and overexpression of netrin-1, which phosphorylates and inactivates POPDC1, are the four primary mechanisms of PODPC1 downregulation. HCC, CRC, BC, PC, NSCLC, HNSCC, and glioma are only a few of the cancers that have been linked to these processes. Promoter hypermethylation is the most well-studied mechanism for POPDC1 downregulation. Many downstream proteins, such as ZO-1, occludin, LRP6, and PR61α, interact with the POPDC1 protein. This interaction has been shown primarily in cardiac and skeletal muscle cells. However, evidence suggesting POPDC1 interacts with these targets in cancer cells is accumulating. POPDC2 and POPDC3 expression vary depending on the type of cancer. POPDC2 dysregulation is mostly seen in heart disease and breast cancer. POPDC3 mutations have been linked to limb girdle muscular dystrophy and have been proven to have tumor-suppressive and oncogenic effects in various cancers. Abbreviations: VASP, vasodilator-stimulated-phosphoprotein; PARP1, cAMP-induced poly [ADP-ribose] polymerase 1; Bcl-Xl, B-cell lymphoma-extra-large; PRKACA, catalytic subunit of PKA C (DNAJB1-protein kinase cAMP-activated catalytic subunit alpha); CIP4, CDC42-interacting protein 4; BC, breast cancer; CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small-cell lung cancer; PC, prostate cancer, HCE, human corneal epithelial cell; HEK293, HEK cells. ↑ shows increased expression, and ↓ shows decreased expression of various targets.