Cargando…
Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth
Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351684/ https://www.ncbi.nlm.nih.gov/pubmed/28036303 http://dx.doi.org/10.18632/oncotarget.14346 |
_version_ | 1782514813171138560 |
---|---|
author | Xiangyun, Ye Xiaomin, Niu linping, Gu Yunhua, Xu Ziming, Li Yongfeng, Yu Zhiwei, Chen Shun, Lu |
author_facet | Xiangyun, Ye Xiaomin, Niu linping, Gu Yunhua, Xu Ziming, Li Yongfeng, Yu Zhiwei, Chen Shun, Lu |
author_sort | Xiangyun, Ye |
collection | PubMed |
description | Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research. |
format | Online Article Text |
id | pubmed-5351684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53516842017-04-13 Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth Xiangyun, Ye Xiaomin, Niu linping, Gu Yunhua, Xu Ziming, Li Yongfeng, Yu Zhiwei, Chen Shun, Lu Oncotarget Research Paper Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research. Impact Journals LLC 2016-12-28 /pmc/articles/PMC5351684/ /pubmed/28036303 http://dx.doi.org/10.18632/oncotarget.14346 Text en Copyright: © 2017 Xiangyun 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Xiangyun, Ye Xiaomin, Niu linping, Gu Yunhua, Xu Ziming, Li Yongfeng, Yu Zhiwei, Chen Shun, Lu Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth |
title | Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth |
title_full | Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth |
title_fullStr | Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth |
title_full_unstemmed | Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth |
title_short | Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth |
title_sort | desuccinylation of pyruvate kinase m2 by sirt5 contributes to antioxidant response and tumor growth |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351684/ https://www.ncbi.nlm.nih.gov/pubmed/28036303 http://dx.doi.org/10.18632/oncotarget.14346 |
work_keys_str_mv | AT xiangyunye desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT xiaominniu desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT linpinggu desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT yunhuaxu desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT zimingli desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT yongfengyu desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT zhiweichen desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth AT shunlu desuccinylationofpyruvatekinasem2bysirt5contributestoantioxidantresponseandtumorgrowth |