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Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer
Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contrib...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741592/ https://www.ncbi.nlm.nih.gov/pubmed/26439801 |
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author | Li, Wei Ma, Zhenhua Ma, Jiguang Li, Xuqi Xu, Qinhong Duan, Wanxing Chen, Xin Lv, Yunfu Zhou, Shuang Wu, Erxi Ma, Qingyong Huo, Xiongwei |
author_facet | Li, Wei Ma, Zhenhua Ma, Jiguang Li, Xuqi Xu, Qinhong Duan, Wanxing Chen, Xin Lv, Yunfu Zhou, Shuang Wu, Erxi Ma, Qingyong Huo, Xiongwei |
author_sort | Li, Wei |
collection | PubMed |
description | Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contributes to their enhanced metastatic behavior. Here we show that hyperglycemia increases the hydrogen peroxide (H(2)O(2)) concentration through up-regulation of manganese superoxide dismutase (SOD2) expression, which further activates the ERK and p38 MAPK pathways, as well as the transcription factors NF-κB and AP-1, in a time-dependent manner. The invasion of pancreatic cancer cells resulting from the activation of the H(2)O(2)/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2. In addition, streptozotocin-treated diabetic nude mice exhibit a stronger tumor invasive ability in renal capsule xenografts which could be suppressed by PEG-CAT treatment. Furthermore, the integrated optical density (IOD) of SOD2 and uPA stainings is higher in the tumor tissues of pancreatic cancer patients with diabetes compared with pancreatic cancer patients with euglycemia. Taken together, our results demonstrate that hyperglycemia enhances cell invasive ability through the SOD2/H(2)O(2)/MAPK axis in human pancreatic cancer. Thus, SOD2/H(2)O(2)/MAPK axis may represent a promising therapeutic target for pancreatic cancer patients combined with diabetes mellitus. |
format | Online Article Text |
id | pubmed-4741592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-47415922016-03-03 Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer Li, Wei Ma, Zhenhua Ma, Jiguang Li, Xuqi Xu, Qinhong Duan, Wanxing Chen, Xin Lv, Yunfu Zhou, Shuang Wu, Erxi Ma, Qingyong Huo, Xiongwei Oncotarget Research Paper Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contributes to their enhanced metastatic behavior. Here we show that hyperglycemia increases the hydrogen peroxide (H(2)O(2)) concentration through up-regulation of manganese superoxide dismutase (SOD2) expression, which further activates the ERK and p38 MAPK pathways, as well as the transcription factors NF-κB and AP-1, in a time-dependent manner. The invasion of pancreatic cancer cells resulting from the activation of the H(2)O(2)/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2. In addition, streptozotocin-treated diabetic nude mice exhibit a stronger tumor invasive ability in renal capsule xenografts which could be suppressed by PEG-CAT treatment. Furthermore, the integrated optical density (IOD) of SOD2 and uPA stainings is higher in the tumor tissues of pancreatic cancer patients with diabetes compared with pancreatic cancer patients with euglycemia. Taken together, our results demonstrate that hyperglycemia enhances cell invasive ability through the SOD2/H(2)O(2)/MAPK axis in human pancreatic cancer. Thus, SOD2/H(2)O(2)/MAPK axis may represent a promising therapeutic target for pancreatic cancer patients combined with diabetes mellitus. Impact Journals LLC 2015-09-05 /pmc/articles/PMC4741592/ /pubmed/26439801 Text en Copyright: © 2015 Li et al. http://creativecommons.org/licenses/by/2.5/ 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 Li, Wei Ma, Zhenhua Ma, Jiguang Li, Xuqi Xu, Qinhong Duan, Wanxing Chen, Xin Lv, Yunfu Zhou, Shuang Wu, Erxi Ma, Qingyong Huo, Xiongwei Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer |
title | Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer |
title_full | Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer |
title_fullStr | Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer |
title_full_unstemmed | Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer |
title_short | Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer |
title_sort | hydrogen peroxide mediates hyperglycemia-induced invasive activity via erk and p38 mapk in human pancreatic cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741592/ https://www.ncbi.nlm.nih.gov/pubmed/26439801 |
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