GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment.

Autor: Worley BL; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Kim YS; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Mardini J; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Zaman R; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Leon KE; Department of Molecular and Cellular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Vallur PG; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Nduwumwami A; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Warrick JI; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Timmins PF; Womens Cancer Care Associates, Albany, NY, USA., Kesterson JP; Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Phaëton R; Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Lee NY; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA., Walter V; Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Endres L; Department of Biology and Chemistry, SUNY Polytechnic Institute, Utica, NY, USA., Mythreye K; Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA., Aird KM; Department of Molecular and Cellular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Hempel N; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: nhempel@psu.edu.
Jazyk: angličtina
Zdroj: Redox biology [Redox Biol] 2019 Jul; Vol. 25, pp. 101051. Date of Electronic Publication: 2018 Nov 17.
DOI: 10.1016/j.redox.2018.11.009
Abstrakt: Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H 2 O 2 . Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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