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Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()

Enhanced autophagy has been observed in hypoxic regions of solid tumors. Here we address the hypothesis that autophagy is required for survival of hypoxic cells. We evaluated sensitivity to hypoxia of three human tumor cell lines (MCF7, PC3, and LNCaP) and their autophagy-deficient variants with shR...

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Autores principales: Tan, Qian, Wang, Marina, Yu, Man, Zhang, Junyan, Bristow, Robert G, Hill, Richard P, Tannock, Ian F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909700/
https://www.ncbi.nlm.nih.gov/pubmed/27292024
http://dx.doi.org/10.1016/j.neo.2016.04.003
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author Tan, Qian
Wang, Marina
Yu, Man
Zhang, Junyan
Bristow, Robert G
Hill, Richard P
Tannock, Ian F
author_facet Tan, Qian
Wang, Marina
Yu, Man
Zhang, Junyan
Bristow, Robert G
Hill, Richard P
Tannock, Ian F
author_sort Tan, Qian
collection PubMed
description Enhanced autophagy has been observed in hypoxic regions of solid tumors. Here we address the hypothesis that autophagy is required for survival of hypoxic cells. We evaluated sensitivity to hypoxia of three human tumor cell lines (MCF7, PC3, and LNCaP) and their autophagy-deficient variants with shRNA knockdown of the genes ATG7 and BECLIN1. Hypoxia-induced cell death was more rapid for autophagy-deficient cells and was increased in the presence of the proton pump inhibitor pantoprazole that inhibits autophagy. Autophagy-deficient cells had a lower rate of oxygen consumption than wild-type cells. In xenografts derived from the three cell lines, autophagy (as determined by increased LC3 and reduced p62/SQSTM1) colocalized with hypoxic regions (identified by EF5). Xenografts derived from autophagy-deficient cells grew more slowly than wild-type tumors. Both LC3 expression and hypoxia were decreased in xenografts generated from single-knockdown cells and absent in double-knockdown tumors. Our results are consistent with the hypothesis that autophagy facilitates the survival of hypoxic cells, although reduced oxygen consumption of autophagy-deficient cells may contribute to lack of hypoxia in tumors derived from them. Because hypoxia is associated with resistance to anticancer therapy, inhibition of autophagy has potential to enhance the effectiveness of cancer treatment.
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spelling pubmed-49097002016-06-22 Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()() Tan, Qian Wang, Marina Yu, Man Zhang, Junyan Bristow, Robert G Hill, Richard P Tannock, Ian F Neoplasia Article Enhanced autophagy has been observed in hypoxic regions of solid tumors. Here we address the hypothesis that autophagy is required for survival of hypoxic cells. We evaluated sensitivity to hypoxia of three human tumor cell lines (MCF7, PC3, and LNCaP) and their autophagy-deficient variants with shRNA knockdown of the genes ATG7 and BECLIN1. Hypoxia-induced cell death was more rapid for autophagy-deficient cells and was increased in the presence of the proton pump inhibitor pantoprazole that inhibits autophagy. Autophagy-deficient cells had a lower rate of oxygen consumption than wild-type cells. In xenografts derived from the three cell lines, autophagy (as determined by increased LC3 and reduced p62/SQSTM1) colocalized with hypoxic regions (identified by EF5). Xenografts derived from autophagy-deficient cells grew more slowly than wild-type tumors. Both LC3 expression and hypoxia were decreased in xenografts generated from single-knockdown cells and absent in double-knockdown tumors. Our results are consistent with the hypothesis that autophagy facilitates the survival of hypoxic cells, although reduced oxygen consumption of autophagy-deficient cells may contribute to lack of hypoxia in tumors derived from them. Because hypoxia is associated with resistance to anticancer therapy, inhibition of autophagy has potential to enhance the effectiveness of cancer treatment. Neoplasia Press 2016-06-09 /pmc/articles/PMC4909700/ /pubmed/27292024 http://dx.doi.org/10.1016/j.neo.2016.04.003 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Tan, Qian
Wang, Marina
Yu, Man
Zhang, Junyan
Bristow, Robert G
Hill, Richard P
Tannock, Ian F
Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()
title Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()
title_full Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()
title_fullStr Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()
title_full_unstemmed Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()
title_short Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors()()
title_sort role of autophagy as a survival mechanism for hypoxic cells in tumors()()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909700/
https://www.ncbi.nlm.nih.gov/pubmed/27292024
http://dx.doi.org/10.1016/j.neo.2016.04.003
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