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Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic...

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Autores principales: Tran, Thai Q., Ishak Gabra, Mari B., Lowman, Xazmin H., Yang, Ying, Reid, Michael A., Pan, Min, O’Connor, Timothy R., Kong, Mei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673162/
https://www.ncbi.nlm.nih.gov/pubmed/29107960
http://dx.doi.org/10.1371/journal.pbio.2002810
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author Tran, Thai Q.
Ishak Gabra, Mari B.
Lowman, Xazmin H.
Yang, Ying
Reid, Michael A.
Pan, Min
O’Connor, Timothy R.
Kong, Mei
author_facet Tran, Thai Q.
Ishak Gabra, Mari B.
Lowman, Xazmin H.
Yang, Ying
Reid, Michael A.
Pan, Min
O’Connor, Timothy R.
Kong, Mei
author_sort Tran, Thai Q.
collection PubMed
description Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.
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spelling pubmed-56731622017-11-18 Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes Tran, Thai Q. Ishak Gabra, Mari B. Lowman, Xazmin H. Yang, Ying Reid, Michael A. Pan, Min O’Connor, Timothy R. Kong, Mei PLoS Biol Research Article Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer. Public Library of Science 2017-11-06 /pmc/articles/PMC5673162/ /pubmed/29107960 http://dx.doi.org/10.1371/journal.pbio.2002810 Text en © 2017 Tran et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tran, Thai Q.
Ishak Gabra, Mari B.
Lowman, Xazmin H.
Yang, Ying
Reid, Michael A.
Pan, Min
O’Connor, Timothy R.
Kong, Mei
Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes
title Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes
title_full Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes
title_fullStr Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes
title_full_unstemmed Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes
title_short Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes
title_sort glutamine deficiency induces dna alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of alkbh enzymes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673162/
https://www.ncbi.nlm.nih.gov/pubmed/29107960
http://dx.doi.org/10.1371/journal.pbio.2002810
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