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PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer
The aim of this study was to explore the efficacy of mTOR inhibitor for castration-resistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021245/ https://www.ncbi.nlm.nih.gov/pubmed/29963230 http://dx.doi.org/10.18632/oncotarget.25498 |
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author | Yasumizu, Yota Hongo, Hiroshi Kosaka, Takeo Mikami, Shuji Nishimoto, Koshiro Kikuchi, Eiji Oya, Mototsugu |
author_facet | Yasumizu, Yota Hongo, Hiroshi Kosaka, Takeo Mikami, Shuji Nishimoto, Koshiro Kikuchi, Eiji Oya, Mototsugu |
author_sort | Yasumizu, Yota |
collection | PubMed |
description | The aim of this study was to explore the efficacy of mTOR inhibitor for castration-resistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC. |
format | Online Article Text |
id | pubmed-6021245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-60212452018-06-29 PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer Yasumizu, Yota Hongo, Hiroshi Kosaka, Takeo Mikami, Shuji Nishimoto, Koshiro Kikuchi, Eiji Oya, Mototsugu Oncotarget Research Paper The aim of this study was to explore the efficacy of mTOR inhibitor for castration-resistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC. Impact Journals LLC 2018-06-12 /pmc/articles/PMC6021245/ /pubmed/29963230 http://dx.doi.org/10.18632/oncotarget.25498 Text en Copyright: © 2018 Yasumizu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yasumizu, Yota Hongo, Hiroshi Kosaka, Takeo Mikami, Shuji Nishimoto, Koshiro Kikuchi, Eiji Oya, Mototsugu PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer |
title | PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer |
title_full | PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer |
title_fullStr | PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer |
title_full_unstemmed | PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer |
title_short | PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer |
title_sort | pkm2 under hypoxic environment causes resistance to mtor inhibitor in human castration resistant prostate cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021245/ https://www.ncbi.nlm.nih.gov/pubmed/29963230 http://dx.doi.org/10.18632/oncotarget.25498 |
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