Progesterone is a growth inhibitory
hormone in the endometrium. While
progestins can be used for the treatment of well-differentiated
endometrial cancers, resistance to
progestin therapy occurs for reasons that remain unclear. We have previously demonstrated that
progesterone receptors (PR) A and B differentially regulate apoptosis in response to overexpression of the
forkhead transcription factor, FOXO1. In this study, we further examined the PR-
isoform-dependent cellular response to the AKT pathway. Treatment of PRA and PRB-expressing Ishikawa cells (PRA14, PRB23), with an AKT inhibitor
API-59CJ-OMe (API-59) promoted apoptosis in the presence and absence of the
ligand,
R5020 preferentially in PRA14 cells. Upon PR knockdown using
small interfering RNA, an increase in apoptosis was observed in PRB23 cells treated with API-59 with or without
R5020 while there was no influence in PRA14 cells. Using an apoptosis-focused real-time PCR array, genes regulated by API-59 and
R5020 were identified both common and unique to PRA14 and PRB23 cells. BIRC3 was identified as the only gene regulated by
R5020 which occurred only in PRB cells. Knockdown of BIRC3 in PRB23 cells promoted a decrease in cell viability in response to API-59 +
R5020. Furthermore, the important role of inhibitors of apoptosis (IAPs) in the PRB23 cells to promote cell survival was demonstrated using an antagonist to IAPs, a second mitochondria-derived activator of
caspase (Smac also known as DIABLO) mimetic. Treatment of PRB23 cells with Smac mimetic increased apoptosis in response to API-59 +
R5020. In summary, our findings indicate a mechanism by which PRB can promote cell survival in the setting of high AKT activity in
endometrial cancer cells.