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Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2
Pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms underlying such a role of PKM2 remain elusive. Here we show that PKM2 translocates...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339831/ https://www.ncbi.nlm.nih.gov/pubmed/28035139 http://dx.doi.org/10.1038/cr.2016.159 |
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author | Liang, Ji Cao, Ruixiu Wang, Xiongjun Zhang, Yajuan Wang, Pan Gao, Hong Li, Chen Yang, Fan Zeng, Rong Wei, Ping Li, Dawei Li, Wenfeng Yang, Weiwei |
author_facet | Liang, Ji Cao, Ruixiu Wang, Xiongjun Zhang, Yajuan Wang, Pan Gao, Hong Li, Chen Yang, Fan Zeng, Rong Wei, Ping Li, Dawei Li, Wenfeng Yang, Weiwei |
author_sort | Liang, Ji |
collection | PubMed |
description | Pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms underlying such a role of PKM2 remain elusive. Here we show that PKM2 translocates to mitochondria under oxidative stress. In the mitochondria, PKM2 interacts with and phosphorylates Bcl2 at threonine (T) 69. This phosphorylation prevents the binding of Cul3-based E3 ligase to Bcl2 and subsequent degradation of Bcl2. A chaperone protein, HSP90α1, is required for this function of PKM2. HSP90α1's ATPase activity launches a conformational change of PKM2 and facilitates interaction between PKM2 and Bcl2. Replacement of wild-type Bcl2 with phosphorylation-deficient Bcl2 T69A mutant sensitizes glioma cells to oxidative stress-induced apoptosis and impairs brain tumor formation in an orthotopic xenograft model. Notably, a peptide that is composed of the amino acid residues from 389 to 405 of PKM2, through which PKM2 binds to Bcl2, disrupts PKM2-Bcl2 interaction, promotes Bcl2 degradation and impairs brain tumor growth. In addition, levels of Bcl2 T69 phosphorylation, conformation-altered PKM2 and Bcl2 protein correlate with one another in specimens of human glioblastoma patients. Moreover, levels of Bcl2 T69 phosphorylation and conformation-altered PKM2 correlate with both grades and prognosis of glioma malignancy. Our findings uncover a novel mechanism through which mitochondrial PKM2 phosphorylates Bcl2 and inhibits apoptosis directly, highlight the essential role of PKM2 in ROS adaptation of cancer cells, and implicate HSP90-PKM2-Bcl2 axis as a potential target for therapeutic intervention in glioblastoma. |
format | Online Article Text |
id | pubmed-5339831 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53398312017-03-09 Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 Liang, Ji Cao, Ruixiu Wang, Xiongjun Zhang, Yajuan Wang, Pan Gao, Hong Li, Chen Yang, Fan Zeng, Rong Wei, Ping Li, Dawei Li, Wenfeng Yang, Weiwei Cell Res Original Article Pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms underlying such a role of PKM2 remain elusive. Here we show that PKM2 translocates to mitochondria under oxidative stress. In the mitochondria, PKM2 interacts with and phosphorylates Bcl2 at threonine (T) 69. This phosphorylation prevents the binding of Cul3-based E3 ligase to Bcl2 and subsequent degradation of Bcl2. A chaperone protein, HSP90α1, is required for this function of PKM2. HSP90α1's ATPase activity launches a conformational change of PKM2 and facilitates interaction between PKM2 and Bcl2. Replacement of wild-type Bcl2 with phosphorylation-deficient Bcl2 T69A mutant sensitizes glioma cells to oxidative stress-induced apoptosis and impairs brain tumor formation in an orthotopic xenograft model. Notably, a peptide that is composed of the amino acid residues from 389 to 405 of PKM2, through which PKM2 binds to Bcl2, disrupts PKM2-Bcl2 interaction, promotes Bcl2 degradation and impairs brain tumor growth. In addition, levels of Bcl2 T69 phosphorylation, conformation-altered PKM2 and Bcl2 protein correlate with one another in specimens of human glioblastoma patients. Moreover, levels of Bcl2 T69 phosphorylation and conformation-altered PKM2 correlate with both grades and prognosis of glioma malignancy. Our findings uncover a novel mechanism through which mitochondrial PKM2 phosphorylates Bcl2 and inhibits apoptosis directly, highlight the essential role of PKM2 in ROS adaptation of cancer cells, and implicate HSP90-PKM2-Bcl2 axis as a potential target for therapeutic intervention in glioblastoma. Nature Publishing Group 2017-03 2016-12-30 /pmc/articles/PMC5339831/ /pubmed/28035139 http://dx.doi.org/10.1038/cr.2016.159 Text en Copyright © 2016 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Liang, Ji Cao, Ruixiu Wang, Xiongjun Zhang, Yajuan Wang, Pan Gao, Hong Li, Chen Yang, Fan Zeng, Rong Wei, Ping Li, Dawei Li, Wenfeng Yang, Weiwei Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 |
title | Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 |
title_full | Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 |
title_fullStr | Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 |
title_full_unstemmed | Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 |
title_short | Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2 |
title_sort | mitochondrial pkm2 regulates oxidative stress-induced apoptosis by stabilizing bcl2 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339831/ https://www.ncbi.nlm.nih.gov/pubmed/28035139 http://dx.doi.org/10.1038/cr.2016.159 |
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