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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Biology and Signal Transduction

Alkylating Agent–Induced NRF2 Blocks Endoplasmic Reticulum Stress–Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis

Alfeu Zanotto-Filho, V. Pragathi Masamsetti, Eva Loranc, Sonal S. Tonapi, Aparna Gorthi, Xavier Bernard, Rosângela Mayer Gonçalves, José C.F. Moreira, Yidong Chen and Alexander J.R. Bishop
Alfeu Zanotto-Filho
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
2Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
3Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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V. Pragathi Masamsetti
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
4Children's Medical Research Institute, Westmead, New South Wales, Australia.
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Eva Loranc
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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Sonal S. Tonapi
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
5Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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Aparna Gorthi
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
5Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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Xavier Bernard
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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Rosângela Mayer Gonçalves
3Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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José C.F. Moreira
3Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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Yidong Chen
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
6Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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Alexander J.R. Bishop
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
5Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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  • For correspondence: bishopa@uthscsa.edu
DOI: 10.1158/1535-7163.MCT-16-0271 Published December 2016
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Abstract

Alkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis, and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival, an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine or glutathione-ethyl-ester, decreased ER stress and abrogated alkylating agents–induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 target overexpression and poor survival. In KEAP1-mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity. Mol Cancer Ther; 15(12); 3000–14. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received May 3, 2016.
  • Revision received August 17, 2016.
  • Accepted August 25, 2016.
  • ©2016 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 15 (12)
December 2016
Volume 15, Issue 12
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Alkylating Agent–Induced NRF2 Blocks Endoplasmic Reticulum Stress–Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis
Alfeu Zanotto-Filho, V. Pragathi Masamsetti, Eva Loranc, Sonal S. Tonapi, Aparna Gorthi, Xavier Bernard, Rosângela Mayer Gonçalves, José C.F. Moreira, Yidong Chen and Alexander J.R. Bishop
Mol Cancer Ther December 1 2016 (15) (12) 3000-3014; DOI: 10.1158/1535-7163.MCT-16-0271

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Alkylating Agent–Induced NRF2 Blocks Endoplasmic Reticulum Stress–Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis
Alfeu Zanotto-Filho, V. Pragathi Masamsetti, Eva Loranc, Sonal S. Tonapi, Aparna Gorthi, Xavier Bernard, Rosângela Mayer Gonçalves, José C.F. Moreira, Yidong Chen and Alexander J.R. Bishop
Mol Cancer Ther December 1 2016 (15) (12) 3000-3014; DOI: 10.1158/1535-7163.MCT-16-0271
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