Cargando…

Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells

OBJECTIVE: Lung cancer is the leading cause of cancer-related death worldwide. Aerobic glycolysis is considered the seventh hallmark of cancer. The M2 isoform of pyruvate kinase (PKM2) is an important rate-limiting enzyme in glycolytic pathway, and is strongly expressed in several types of cancer. T...

Descripción completa

Detalles Bibliográficos
Autores principales: An, Shuxian, Huang, Liangqian, Miao, Ping, Shi, Liang, Shen, Mengqin, Zhao, Xiaoping, Liu, Jianjun, Huang, Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907896/
https://www.ncbi.nlm.nih.gov/pubmed/29713182
http://dx.doi.org/10.2147/OTT.S156918
_version_ 1783315621829672960
author An, Shuxian
Huang, Liangqian
Miao, Ping
Shi, Liang
Shen, Mengqin
Zhao, Xiaoping
Liu, Jianjun
Huang, Gang
author_facet An, Shuxian
Huang, Liangqian
Miao, Ping
Shi, Liang
Shen, Mengqin
Zhao, Xiaoping
Liu, Jianjun
Huang, Gang
author_sort An, Shuxian
collection PubMed
description OBJECTIVE: Lung cancer is the leading cause of cancer-related death worldwide. Aerobic glycolysis is considered the seventh hallmark of cancer. The M2 isoform of pyruvate kinase (PKM2) is an important rate-limiting enzyme in glycolytic pathway, and is strongly expressed in several types of cancer. Thus, understanding the underlying mechanisms of regulation of PKM2 is of great value for targeted therapy for lung cancer. PATIENTS AND METHODS: Seventy-three lung adenocarcinoma patients were analyzed in our study. The expression levels of PKM2 were analyzed by immunohistochemistry on tissues. The effect of small ubiquitin-like modifier 1 (SUMO1) on PKM2 expression was investigated using Western blot assay and quantitative polymerase chain reaction. PKM2 SUMO1 modification was determined by in vitro and in vivo SUMOylation assays. (18)F-deoxyglucose uptake and lactate production measurements were conducted to research the levels of glycolysis. The level of oxidative phosphorylation in cells was determined by cellular oxygen consumption rate measurements. Cell proliferation assays were carried out to confirm the growth ability of tumor cells. RESULTS: PKM2 was overexpressed in lung adenocarcinoma patients based on immunohistochemical staining. Patients with high PKM2 expression had reduced overall survival rate (P=0.017) and disease-free survival rate (P=0.027) compared with those with low PKM2 expression. SUMO1 promoted PKM2-dependent glycolysis. Western blotting analysis showed that SUMO1 knockdown in A549 cells led to a significant decrease in PKM2 protein expression. PKM2 could be covalently modified by SUMO1 at K336 (Lys336) site. SUMO1 modification of PKM2 at Lys-336 site increased glycolysis and promoted its cofactor functions. Moreover, PKM2 SUMO1 modification promoted the proliferation of A549 cells in vitro. CONCLUSION: This information is important in elucidating a new mechanism of regulation of PKM2, and suggested that SUMO1 modification of PKM2 could be a potential therapeutic target in lung cancer.
format Online
Article
Text
id pubmed-5907896
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Dove Medical Press
record_format MEDLINE/PubMed
spelling pubmed-59078962018-04-30 Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells An, Shuxian Huang, Liangqian Miao, Ping Shi, Liang Shen, Mengqin Zhao, Xiaoping Liu, Jianjun Huang, Gang Onco Targets Ther Original Research OBJECTIVE: Lung cancer is the leading cause of cancer-related death worldwide. Aerobic glycolysis is considered the seventh hallmark of cancer. The M2 isoform of pyruvate kinase (PKM2) is an important rate-limiting enzyme in glycolytic pathway, and is strongly expressed in several types of cancer. Thus, understanding the underlying mechanisms of regulation of PKM2 is of great value for targeted therapy for lung cancer. PATIENTS AND METHODS: Seventy-three lung adenocarcinoma patients were analyzed in our study. The expression levels of PKM2 were analyzed by immunohistochemistry on tissues. The effect of small ubiquitin-like modifier 1 (SUMO1) on PKM2 expression was investigated using Western blot assay and quantitative polymerase chain reaction. PKM2 SUMO1 modification was determined by in vitro and in vivo SUMOylation assays. (18)F-deoxyglucose uptake and lactate production measurements were conducted to research the levels of glycolysis. The level of oxidative phosphorylation in cells was determined by cellular oxygen consumption rate measurements. Cell proliferation assays were carried out to confirm the growth ability of tumor cells. RESULTS: PKM2 was overexpressed in lung adenocarcinoma patients based on immunohistochemical staining. Patients with high PKM2 expression had reduced overall survival rate (P=0.017) and disease-free survival rate (P=0.027) compared with those with low PKM2 expression. SUMO1 promoted PKM2-dependent glycolysis. Western blotting analysis showed that SUMO1 knockdown in A549 cells led to a significant decrease in PKM2 protein expression. PKM2 could be covalently modified by SUMO1 at K336 (Lys336) site. SUMO1 modification of PKM2 at Lys-336 site increased glycolysis and promoted its cofactor functions. Moreover, PKM2 SUMO1 modification promoted the proliferation of A549 cells in vitro. CONCLUSION: This information is important in elucidating a new mechanism of regulation of PKM2, and suggested that SUMO1 modification of PKM2 could be a potential therapeutic target in lung cancer. Dove Medical Press 2018-04-13 /pmc/articles/PMC5907896/ /pubmed/29713182 http://dx.doi.org/10.2147/OTT.S156918 Text en © 2018 An et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
An, Shuxian
Huang, Liangqian
Miao, Ping
Shi, Liang
Shen, Mengqin
Zhao, Xiaoping
Liu, Jianjun
Huang, Gang
Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells
title Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells
title_full Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells
title_fullStr Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells
title_full_unstemmed Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells
title_short Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells
title_sort small ubiquitin-like modifier 1 modification of pyruvate kinase m2 promotes aerobic glycolysis and cell proliferation in a549 human lung cancer cells
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907896/
https://www.ncbi.nlm.nih.gov/pubmed/29713182
http://dx.doi.org/10.2147/OTT.S156918
work_keys_str_mv AT anshuxian smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT huangliangqian smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT miaoping smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT shiliang smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT shenmengqin smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT zhaoxiaoping smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT liujianjun smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells
AT huanggang smallubiquitinlikemodifier1modificationofpyruvatekinasem2promotesaerobicglycolysisandcellproliferationina549humanlungcancercells