Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Claudia R Oliva; Susan E Nozell; Anne Diers; Samuel G McClugage; Jann N Sarkaria; James M Markert; Victor M Darley-Usmar; Shannon M Bailey; G. Yancey Gillespie; Aimee Landar; Corinne E Griguer

doi:10.1074/jbc.M110.147504

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Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

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Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Claudia R Oliva, Susan E Nozell, Anne Diers, Samuel G McClugage, Jann N Sarkaria, James M Markert, Victor M Darley-Usmar, Shannon M Bailey, G. Yancey Gillespie, Aimee Landar, …

The Journal of biological chemistry, Vol.285(51), pp.39759-39767

12/17/2010

DOI: 10.1074/jbc.M110.147504

PMCID: PMC3000957

PMID: 20870728

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Abstract

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.

Brain

Cancer Therapy

Cytochrome Oxidase

Electron Transport

Mitochondria

Bioenergetics

Glioma

Chemoresistance

Mitochondrial DNA

Temozolomide

Details

Title: Subtitle: Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain
Creators: Claudia R Oliva - From the
Susan E Nozell - the
Anne Diers - the
Samuel G McClugage - From the
Jann N Sarkaria - the
James M Markert - From the
Victor M Darley-Usmar - the
Shannon M Bailey - the
G. Yancey Gillespie - From the
Aimee Landar - the
Corinne E Griguer - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.285(51), pp.39759-39767
DOI: 10.1074/jbc.M110.147504
PMID: 20870728
PMCID: PMC3000957
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: P30 CA13148-35 / National Institutes of Health
Alternative title: Temozolomide Resistance and Mitochondrial Function
Language: English
Date published: 12/17/2010
Academic Unit: Radiation Oncology
Record Identifier: 9984047639102771

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