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Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy
Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255907/ https://www.ncbi.nlm.nih.gov/pubmed/30478344 http://dx.doi.org/10.1038/s41467-018-07411-7 |
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author | Geng, Hao Xue, Changhui Mendonca, Janet Sun, Xiao-Xin Liu, Qiong Reardon, Patrick N. Chen, Yingxiao Qian, Kendrick Hua, Vivian Chen, Alice Pan, Freddy Yuan, Julia Dang, Sang Beer, Tomasz M. Dai, Mu-Shui Kachhap, Sushant K. Qian, David Z. |
author_facet | Geng, Hao Xue, Changhui Mendonca, Janet Sun, Xiao-Xin Liu, Qiong Reardon, Patrick N. Chen, Yingxiao Qian, Kendrick Hua, Vivian Chen, Alice Pan, Freddy Yuan, Julia Dang, Sang Beer, Tomasz M. Dai, Mu-Shui Kachhap, Sushant K. Qian, David Z. |
author_sort | Geng, Hao |
collection | PubMed |
description | Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo. |
format | Online Article Text |
id | pubmed-6255907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62559072018-11-28 Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy Geng, Hao Xue, Changhui Mendonca, Janet Sun, Xiao-Xin Liu, Qiong Reardon, Patrick N. Chen, Yingxiao Qian, Kendrick Hua, Vivian Chen, Alice Pan, Freddy Yuan, Julia Dang, Sang Beer, Tomasz M. Dai, Mu-Shui Kachhap, Sushant K. Qian, David Z. Nat Commun Article Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo. Nature Publishing Group UK 2018-11-26 /pmc/articles/PMC6255907/ /pubmed/30478344 http://dx.doi.org/10.1038/s41467-018-07411-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Geng, Hao Xue, Changhui Mendonca, Janet Sun, Xiao-Xin Liu, Qiong Reardon, Patrick N. Chen, Yingxiao Qian, Kendrick Hua, Vivian Chen, Alice Pan, Freddy Yuan, Julia Dang, Sang Beer, Tomasz M. Dai, Mu-Shui Kachhap, Sushant K. Qian, David Z. Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy |
title | Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy |
title_full | Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy |
title_fullStr | Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy |
title_full_unstemmed | Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy |
title_short | Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy |
title_sort | interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/ar-targeted therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255907/ https://www.ncbi.nlm.nih.gov/pubmed/30478344 http://dx.doi.org/10.1038/s41467-018-07411-7 |
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