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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2016
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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. |
format | Online Article Text |
id | pubmed-4909700 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
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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