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Increased Expression of System x_c^- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Polewski, Monika D. and Reveron-Thornton, Rosyli F. and Cherryholmes, Gregory A. and Marinov, Georgi K. and Cassady, Kaniel and Aboody, Karen S. (2016) Increased Expression of System x_c^- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance. Molecular Cancer Research, 14 (12). pp. 1229-1242. ISSN 1541-7786. PMCID PMC6237285. https://resolver.caltech.edu/CaltechAUTHORS:20161004-142517367

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Abstract

Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system x_c^-, a transporter involved in cysteine import, that modulates glutathione production and glioma growth. However, the role of system x_c^- in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system x_c^- with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system x_c^- in glioma, stable SLC7A11-knockdown and -overexpressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but overexpression did increase anchorage-independent cell growth. Knockdown of SLC7A11 increased basal reactive oxygen species (ROS) and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Overexpression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 overexpression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation, and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1541-7786.MCR-16-0028DOIArticle
http://mcr.aacrjournals.org/content/14/12/1229PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237285PubMed CentralArticle
ORCID:
AuthorORCID
Marinov, Georgi K.0000-0003-1822-7273
Alternate Title:Increased expression of system x_c^- in glioblastoma confers an altered metabolism and chemoresistance
Additional Information:© 2016 American Association for Cancer Research. Received January 25, 2016; revised August 1, 2016; accepted August 25, 2016; published Online First September 22, 2016. We acknowledge the technical support of the City of Hope RNAi Core (Dr. Claudia M. Kowolik), the Light Microscopy Digital Imaging Core (Dr. Brian Armstrong and Tina Patel), the Electron Microscopy Core, Megan Gilchrist for staining the glioma orthotopic xenograft sections, and Dr. Keely L. Walker for critical reading and editing of the article. Research reported in this publication included work performed in the Integrative Genomics Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by funding from the California Institute of Regenerative Medicine (TG2-01150), the Rosalinde and Arthur Gilbert Foundation, STOP Cancer, and the Cancer Center Support Grant (P30CA033572). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. No potential conflicts of interest were disclosed. Authors' Contributions: Conception and design: M.D. Polewski, R.F. Reveron-Thornton, G.A. Cherryholmes Development of methodology: M.D. Polewski, R.F. Reveron-Thornton, G.A. Cherryholmes Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.D. Polewski, R.F. Reveron-Thornton, K.S. Aboody Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.D. Polewski, R.F. Reveron-Thornton, G.A. Cherryholmes, G.K. Marinov, K. Cassady Writing, review, and/or revision of the manuscript: M.D. Polewski, R.F. Reveron-Thornton, G.A. Cherryholmes, K.S. Aboody Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M.D. Polewski, R.F. Reveron-Thornton, K.S. Aboody Study supervision: M.D. Polewski, K.S. Aboody
Funders:
Funding AgencyGrant Number
NIHP30CA033572
California Institute for Regenerative Medicine (CIRM)TG2-01150
Rosalinde and Arthur Gilbert FoundationUNSPECIFIED
STOP CancerUNSPECIFIED
Subject Keywords:SLC7A11; glioma; oxidative stress; glutathione; chemoresistance, metabolism
Issue or Number:12
PubMed Central ID:PMC6237285
Record Number:CaltechAUTHORS:20161004-142517367
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20161004-142517367
Official Citation:Increased Expression of System xc− in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance Monika D. Polewski, Rosyli F. Reveron-Thornton, Gregory A. Cherryholmes, Georgi K. Marinov, Kaniel Cassady, and Karen S. Aboody Mol Cancer Res December 1 2016 (14) (12) 1229-1242; DOI: 10.1158/1541-7786.MCR-16-0028
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70837
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:04 Oct 2016 23:29
Last Modified:03 Oct 2019 16:01

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