β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG

Phosphodiesterase 10A (PDE10) is an enzyme that degrades cGMP and cAMP, with high expression levels found in the brain striatum, where it plays a significant role in cognition and psychomotor functions. PDE10 inhibitors are currently being developed for treating schizophrenia and Huntington’s disease and are generally well tolerated, likely due to their low expression in most peripheral tissues.

Recent studies revealed elevated levels of PDE10 in colon tumors, showing that silencing PDE10 through siRNA or using small molecule inhibitors can effectively suppress the growth of colon tumor cells while sparing normal colonocytes (Li et al., Oncogene 2015). These findings indicate a potential, yet unrecognized, role of PDE10 in tumorigenesis.

In this report, we demonstrate that the highly specific PDE10 inhibitor Pf-2545920 (MP-10) inhibits colon tumor cell growth at concentrations that also increase cGMP and cAMP levels, subsequently activating PKG and PKA. Additionally, knockdown of PDE10 using shRNA reduces the sensitivity of colon tumor cells to the growth-inhibitory effects of Pf-2545920. The inhibitor also prevents the translocation of β-catenin to the nucleus, leading to a decrease in β-catenin-mediated transcription of survivin, which results in caspase activation and apoptosis. Furthermore, PDE10 mRNA levels were found to be higher in colon tumors compared to normal tissues.

These results suggest that targeting PDE10 could be a viable strategy for cancer therapy or prevention, as its inhibition can elevate cGMP levels and activate PKG, reducing β-catenin-mediated survival protein transcription and promoting selective apoptosis in cancer cells.