title: Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells.
abstract: Loss of nuclear progesterone receptors (PR) and low circulating progesterone levels are associated with increased ovarian cancer (OC) risk. However, PR are abundantly expressed in a significant percentage of serous and endometrioid ovarian tumors; patients with PR+ tumors typically experience longer progression-free survival relative to those with PR-null tumors. The molecular mechanisms of these protective effects are poorly understood. To study PR action in OC in the absence of added estrogen (i.e., needed to induce robust PR expression), we created ES-2 OC cells stably expressing vector control or GFP-tagged PR-B (GFP-PR). Progestin (R5020) stimulation of ES-2 cells stably expressing GFP-PR induced cellular senescence characterized by altered cellular morphology, prolonged survival, senescence-associated β-galactosidase activity, G1 cell cycle arrest and upregulation of the cell cycle inhibitor, p21, as well as the Forkhead-box transcription factor, FOXO1; these results repeated in unmodified ER+/PR+ PEO4 OC cells. PR-B and FOXO1 were detected within the same PRE-containing regions of the p21 upstream promoter. Knockdown of p21 resulted in molecular compensation via FOXO1-dependent upregulation of numerous FOXO1 target genes (p15, p16, p27) and an increased rate of senescence. Inhibition of FOXO1 (with AS1842856) or stable FOXO1 knockdown inhibited progestin-induced p21 expression and blocked progestin-induced senescence. Overall, these findings support a role for PR as a tumor suppressor in OC cells, which exhibits inhibitory effects by inducing FOXO1-dependent cellular senescence. Clinical "priming" of the PR-FOXO1-p21 signaling pathway using PR agonists may provide a useful strategy to induce irreversible cell cycle arrest and thereby sensitize OC cells to existing chemotherapies as part of combination "two-step" therapies.
authors.affiliation: Department of Medicine, Hematology, Oncology, and Transplantation Division, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Diep
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Charles
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Peter A
authors.initials: PA
authors.lastname: Argenta
authors.forename: Carol A
authors.initials: CA
authors.lastname: Lange
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011372:Progestins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011372:Progestins; D011980:Receptors, Progesterone; D049452:Green Fluorescent Proteins
keywords: AS1842856; FOXO1; breast cancer; forkhead transcription factor; ovarian cancer; p21; progesterone receptor; progestin; senescence