title: Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells.
abstract: Cancer stem cells are responsible for tumor initiation and chemoresistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the ovarian cancer stem cells are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of ovarian cancer stem cells. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and by increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of cellular starvation that activates two independent pathways: (i) AMPKα1 pathway leading to mTOR inhibition; and (ii) mitochondrial MAP/ERK kinase/extracellular signal-regulated kinase pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemoresistant cell population opens a new venue for treating ovarian cancer patients.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Ayesha B
authors.initials: AB
authors.lastname: Alvero
authors.forename: Michele K
authors.initials: MK
authors.lastname: Montagna
authors.forename: Jennie C
authors.initials: JC
authors.lastname: Holmberg
authors.forename: Vinicius
authors.initials: V
authors.lastname: Craveiro
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D016923:Cell Death / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D007529:Isoflavones; C542773:NV-128 isoflavone; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D042967:Electron Transport Complex I