GADD45A is a mediator of CD437 induced apoptosis in ovarian carcinoma cells.

Ovarian cancer is one of the leading causes of cancer death in women. A number of studies have suggested that synthetic retinoids may play an important role as an ovarian cancer chemotherapeutic agent. The synthetic retinoid CD 437 induces apoptosis in ovarian tumor cells by a mechanism that is not completely understood. In this study we demonstrate that CD437 treatment leads to an increase in GADD45A and GADD45B mRNA expression in CA-OV3 cells but not in CA-CD437R cells, a cell line which is resistant to CD437. This induction is specific to CD437 since no change in expression of either GADD45A or GADD45B was observed with either all-trans-RA or 4-HPR treatment. Western blot analysis demonstrated that the induction of GADD45A mRNA in the CA-OV3 cell line by CD437 was accompanied by an increase in GADD45A protein. Upregulation of GADD45A by CD437 is regulated at least in part at the post-transcriptional level. In contrast, CD437 regulates GADD45B expression by different mechanisms. The importance of GADD45A induction in mediating apoptosis was demonstrated in CA-OV3 cells overexpressing GADD45A antisense RNA (GADD45A-AS cells). Our results suggest that induction of GADD45A expression might play a role in mediating the apoptotic response of ovarian cancer cells to the synthetic retinoid CD437.