Autotaxin regulates maintenance of ovarian cancer stem cells through lysophosphatidic acid-mediated autocrine mechanism

Eun Jin Seo, Yang Woo Kwon, Il Ho Jang, Dae Kyoung Kim, Soo In Lee, Eun Jung Choi, Ki Hyung Kim, Dong Soo Suh, Jeong Hee Lee, Kyung Un Choi, Jae Won Lee, Hyuck Jun Mok, Kwang Pyo Kim, Hirotaka Matsumoto, Junken Aoki, Jae Ho Kim

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)551-564
Number of pages14
JournalStem Cells
Volume34
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

Keywords

  • Aldehyde dehydrogenase
  • Autotaxin
  • Cancer stem cells
  • Epithelial ovarian cancer
  • Lysophosphatidic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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