title: Akt regulates progesterone receptor B-dependent transcription and angiogenesis in endometrial cancer cells.
abstract: Progestins have long been used clinically for the treatment of endometrial cancers; however, the response rates to progestin therapy vary and the molecular mechanisms behind progestin insensitivity are poorly understood. We hypothesized that in PTEN-mutated endometrial cancers, hyperactive Akt signaling downregulates progesterone receptor B (PRB) transcriptional activity, leading to overall impaired progestin responses. We report that inhibition of Akt with the Akt inhibitor, MK-2206 (MK), in conjunction with progestin (R5020) treatment, is sufficient to upregulate a subset of PRB target genes in Ishikawa cells stably expressing PRB (PRB-Ishikawa). Through gene ontology analysis of Akt-regulated PRB target genes, angiogenesis was found to be the principle process regulated by Akt-PRB. To further interrogate the mechanism by which Akt modulates PRB transcriptional activity, ChIP-Mass spectrometry was performed to identify potential cofactors that differentially interact with PRB in the presence of R5020 and MK+R5020. 14-3-3σ was identified as a protein enriched in the MK+R5020 data set, and it was demonstrated that 14-3-3σ is required for the upregulation in PRB target gene expression following inhibition of Akt. To determine the ramifications of MK+R5020 treatment on angiogenesis, in vitro assays were performed and combinatorial MK+R5020 treatment significantly decreased endothelial cell invasion and tube formation more than MK or R5020 treatment alone. Furthermore, we found that combinatorial MK-2206+progesterone treatments decreased angiogenesis and proliferation in the Pten(d/d) conditional mouse model of endometrial cancer. Taken together, these findings suggest that a combinatorial therapeutic approach utilizing Akt inhibitors with progestins may improve the efficacy of progestin therapy for the treatment of endometrial cancer.
authors.affiliation: Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: I I
authors.initials: II
authors.lastname: Lee
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Maniar
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011372:Progestins / Q000008:administration & dosage; D011397:Promegestone / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D011372:Progestins; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D011397:Promegestone; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt