title: Autotaxin Regulates Maintenance of Ovarian Cancer Stem Cells through Lysophosphatidic Acid-Mediated Autocrine Mechanism.
abstract: Ovarian cancer shows high mortality due to development of resistance to chemotherapy and relapse. Cancer stem cells (CSCs) have been suggested to be a major contributor in developing drug resistance and relapse in ovarian cancer. In this study, we isolated CSCs through sphere culture of A2780, SKOV3, OVCAR3 epithelial ovarian cancer cells and primary ovarian cancer cells from patients. We identified heat-stable factors secreted from ovarian CSCs stimulated migration and proliferation of CSCs. Mass spectrometry and ELISA analysis revealed that lysophosphatidic acid (LPA) was significantly elevated in CSC culture media compared with non-CSC culture media. Treatment of CSCs with LPA resulted in augmented CSC characteristics such as sphere-forming ability, resistance to anticancer drugs, tumorigenic potential in xenograft transplantation, and high expression of CSC-associated genes, including OCT4, SOX2, and aldehyde dehydrogenase 1. Treatment of CSCs with LPA receptor 1-specific inhibitors or silencing of LPA receptor 1 expression abrogated the LPA-stimulated CSC properties. Autotaxin, an LPA-producing enzyme, is highly secreted from ovarian CSCs, and pharmacological inhibition or knockdown of autotaxin markedly attenuated the LPA-producing, tumorigenic, and drug resistance potentials of CSCs. Clinicopathological analysis showed a significant survival disadvantage of patients with positive staining of autotaxin. In addition, we further identified that AKT1 activity was upregulated in ovarian CSCs through an LPA-dependent mechanism and silencing of AKT1 expression led to suppression of CSC characteristics. These results suggest that autotaxin-LPA-LPA receptor 1-AKT1 signaling axis is critical for maintaining CSC characteristics through an autocrine loop and provide a novel therapeutic target for ovarian CSCs.
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Seo
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Yang Woo
authors.initials: YW
authors.lastname: Kwon
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Il Ho
authors.initials: IH
authors.lastname: Jang
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Dae Kyoung
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Soo In
authors.initials: SI
authors.lastname: Lee
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Ki-Hyung
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Dong-Soo
authors.initials: DS
authors.lastname: Suh
authors.affiliation: Department of Pathology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Kyung Un
authors.initials: KU
authors.lastname: Choi
authors.affiliation: Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Hyuck Jun
authors.initials: HJ
authors.lastname: Mok
authors.affiliation: Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Department of Physiology, Pusan National University, Yangsan, Republic of Korea.|Research Institute of Convergence Biomedical Science and Technology, Pusan National University, Yangsan Hospital, Yangsan, Republic of Korea.
authors.forename: Jae Ho
authors.identifier: http://orcid.org/0000-0003-4323-4790
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000067696:Ataxin-1 / Q000235:genetics; D019898:Autocrine Communication / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000008:administration & dosage*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000099189:Lysophospholipase D
chemical_list: D000067696:Ataxin-1; D017077:Culture Media, Conditioned; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C000593749:ATXN1 protein, human; C000609549:LPAR1 protein, human; C494918:AKT1 protein, human; C032881:lysophosphatidic acid
keywords: Aldehyde dehydrogenase; Autotaxin; Cancer stem cells; Epithelial ovarian cancer; Lysophosphatidic acid