Role of cyclic nucleotide phosphodiesterases in cancer

摘要

Type 4 cyclic nucleotide phosphodiesterases (PDE4s) comprise a family of isoenzymes that hydrolyze the second messenger cAMP. Recent studies have shown that treatment with non-selective PDE4 inhibitors impairs cancer cell proliferation, and migration in various cancers, suggesting that PDE4s represent a potential target for development of novel cancer therapeutics. However, non-selective PDE4 inhibitors induce multiple side effects, including nausea, emesis, diarrhea, and weight loss that limit their clinical utility. The PDE4 family comprises four subtypes/genes, PDE4A to D. As each plays unique and non-overlapping physiological and pathophysiological roles in the body, targeting individual PDE4 subtypes may serve to dissect the therapeutic benefits from the current side effects. To this end, we explored the role of PDE4s in five human colon cancer cell lines, and revealed that PDE4 activity and protein in colon cancer cells is largely due to PDE4D, with none of the other PDE4 subtypes (PDE4A-C) being expressed in four of the five cell lines. As these cells exclusively express PDE4D, the effect of non-selective PDE4 inhibitors on cell viability/motility must be mediated via inhibition of PDE4D, thus identifying PDE4D as the preferred target for development of a therapeutic. Current and future studies will be testing this hypothesis by assessing the effect of selective PDE4D inhibition on cancer cell functions.