title: Progesterone receptor-B induction of BIRC3 protects endometrial cancer cells from AP1-59-mediated apoptosis.
abstract: 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.
authors.affiliation: Division of Gynecologic Oncology, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Nikki L
authors.initials: NL
authors.lastname: Neubauer
authors.forename: Erin C
authors.initials: EC
authors.lastname: Ward
authors.forename: Parin
authors.initials: P
authors.lastname: Patel
authors.forename: Zhenxiao
authors.initials: Z
authors.lastname: Lu
authors.forename: Irene
authors.initials: I
authors.lastname: Lee
authors.forename: Leen J
authors.initials: LJ
authors.lastname: Blok
authors.forename: Payman
authors.initials: P
authors.lastname: Hanifi-Moghaddam
authors.forename: Julian
authors.initials: J
authors.lastname: Schink
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D004611:Ellipticines / Q000494:pharmacology*; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: C494380:9-methoxy-2-methylellipticinium acetate; D004611:Ellipticines; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt