title: Adipocyte microenvironment promotes Bclxlexpression and confers chemoresistance in ovarian cancer cells.
abstract: Resistance to mitochondria-initiated apoptosis is a hallmark of chemoresistant cancer stem cells including CD44+/MyD88+ epithelial ovarian cancer (EOC) stem cells. This is controlled by members of the Bcl2family of proteins, which function as rheostats of mitochondrial stability. We observed a differential expression profile of Bcl2family members comparing the chemoresistant EOC stem cells and the chemosensitive CD44-/MyD88- EOC cells. Chemoresistant EOC stem cells surprisingly express higher levels of the pro-apoptotic members Bak and Bax compared to the chemosensitive EOC cells. In addition, whereas chemosensitive EOC cells preferentially express Bcl2, chemoresistant EOC stem cells preferentially express Bclxl. In the EOC stem cells, 40% knock-down of Bclxlexpression was sufficient to induce the full activation of caspases and this can be reversed by concurrent knock-down of Puma. More importantly, we demonstrate that Bclxlexpression levels in EOC cells is dynamic and can be regulated by microenvironments that are enriched with the pro-inflammatory cytokine IL-6 such as the cancer stem cell and adipocyte niches. Adipocyte-induced upregulation of Bclxlcorrelated with acquisition of chemoresistance and thus demonstrates how a specific microenvironment can regulate the expression of apoptotic proteins and confer chemoresistance.
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardenas
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA.
authors.forename: Michele K
authors.initials: MK
authors.lastname: Montagna
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Pitruzzello
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA.
authors.forename: Eydis
authors.initials: E
authors.lastname: Lima
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA. gil.mor@yale.edu.
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA.
authors.forename: Ayesha B
authors.initials: AB
authors.lastname: Alvero
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D016190:Carboplatin / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D060833:Cellular Microenvironment; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016190:Carboplatin; D020169:Caspases
keywords: Adipocyte microenvironment; Bcl2; Bclxl; Chemoresistance; Ovarian cancer stem cells