Cyclic phosphatidic acid decreases proliferation and survival of colon cancer cells by inhibiting peroxisome proliferator-activated receptor γ

Cyclic phosphatidic acid (cPA), a structural analog of lysophosphatidic acid (LPA), is one of the simplest phospholipids found in every cell type. cPA is a specific, high-affinity antagonist of peroxisome proliferator-activated receptor gamma (PPARγ); however, the molecular mechanism by which cPA inhibits cellular proliferation remains to be clarified. In this study, we found that inhibition of PPARγ prevents proliferation of human colon cancer HT-29 cells. cPA suppressed cell growth, and this effect was reversed by the addition of a PPARγ agonist. These results indicate that the physiological effects of cPA are partly due to PPARγ inhibition. Our results identify PPARγ as a molecular mediator of cPA activity in HT-29 cells, and suggest that cPA and the PPARγ pathway might be therapeutic targets in the treatment of colon cancer.

Research highlights▶ cPA inhibits HT-29 colon cancer cell growth by inhibiting PPARγ. ▶ Decreasing PPARγ levels in HT-29 cells with siRNA reduced the cPA dose required to inhibit cell growth. ▶ cPA directly acts on PPARγ in HT-29 cell growth, rather than stimulating an LPA receptors. ▶ Inhibition of HT-29 cell growth by cPA is mediated by its inhibition of the PPARγ pathway.