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Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells

Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT)‐type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms – particularly glycolysis – involved in the regulation of the CSC and EMT...

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Autores principales: Zhao, Hengqiang, Duan, Qingke, Zhang, Zhengle, Li, Hehe, Wu, Heshui, Shen, Qiang, Wang, Chunyou, Yin, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571518/
https://www.ncbi.nlm.nih.gov/pubmed/28244691
http://dx.doi.org/10.1111/jcmm.13126
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author Zhao, Hengqiang
Duan, Qingke
Zhang, Zhengle
Li, Hehe
Wu, Heshui
Shen, Qiang
Wang, Chunyou
Yin, Tao
author_facet Zhao, Hengqiang
Duan, Qingke
Zhang, Zhengle
Li, Hehe
Wu, Heshui
Shen, Qiang
Wang, Chunyou
Yin, Tao
author_sort Zhao, Hengqiang
collection PubMed
description Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT)‐type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms – particularly glycolysis – involved in the regulation of the CSC and EMT phenotypes. We used a gemcitabine‐resistant (GR) Patu8988 cell line, which exhibited clear CSC and EMT phenotypes and showed reliance on glycolysis. Inhibition of glycolysis using 2‐deoxy‐D‐glucose (2‐DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo. Intriguingly, the use of the reactive oxygen species (ROS) scavenger N‐acetylcysteine (NAC) restored the CSC and EMT phenotypes. H(2)O(2) produced changes similar to those of 2‐DG, indicating that ROS were involved in the acquired cancer stemness and EMT phenotypes of GR cells. Moreover, doublecortin‐like kinase 1 (DCLK1), a pancreatic CSC marker, was highly expressed and regulated the stemness and EMT phenotypes in GR cell. Both 2‐DG and H(2)O(2) treatment suppressed DCLK1 expression, which was also rescued by NAC. Together, these findings revealed that glycolysis promotes the expression of DCLK1 and maintains the CSC and EMT phenotypes via maintenance of low ROS levels in chemoresistant GR cells. The glycolysis‐ROS‐DCLK1 pathway may be potential targets for reversing the malignant behaviour of pancreatic cancer.
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spelling pubmed-55715182017-09-01 Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells Zhao, Hengqiang Duan, Qingke Zhang, Zhengle Li, Hehe Wu, Heshui Shen, Qiang Wang, Chunyou Yin, Tao J Cell Mol Med Original Articles Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT)‐type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms – particularly glycolysis – involved in the regulation of the CSC and EMT phenotypes. We used a gemcitabine‐resistant (GR) Patu8988 cell line, which exhibited clear CSC and EMT phenotypes and showed reliance on glycolysis. Inhibition of glycolysis using 2‐deoxy‐D‐glucose (2‐DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo. Intriguingly, the use of the reactive oxygen species (ROS) scavenger N‐acetylcysteine (NAC) restored the CSC and EMT phenotypes. H(2)O(2) produced changes similar to those of 2‐DG, indicating that ROS were involved in the acquired cancer stemness and EMT phenotypes of GR cells. Moreover, doublecortin‐like kinase 1 (DCLK1), a pancreatic CSC marker, was highly expressed and regulated the stemness and EMT phenotypes in GR cell. Both 2‐DG and H(2)O(2) treatment suppressed DCLK1 expression, which was also rescued by NAC. Together, these findings revealed that glycolysis promotes the expression of DCLK1 and maintains the CSC and EMT phenotypes via maintenance of low ROS levels in chemoresistant GR cells. The glycolysis‐ROS‐DCLK1 pathway may be potential targets for reversing the malignant behaviour of pancreatic cancer. John Wiley and Sons Inc. 2017-02-28 2017-09 /pmc/articles/PMC5571518/ /pubmed/28244691 http://dx.doi.org/10.1111/jcmm.13126 Text en © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhao, Hengqiang
Duan, Qingke
Zhang, Zhengle
Li, Hehe
Wu, Heshui
Shen, Qiang
Wang, Chunyou
Yin, Tao
Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells
title Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells
title_full Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells
title_fullStr Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells
title_full_unstemmed Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells
title_short Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells
title_sort up‐regulation of glycolysis promotes the stemness and emt phenotypes in gemcitabine‐resistant pancreatic cancer cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571518/
https://www.ncbi.nlm.nih.gov/pubmed/28244691
http://dx.doi.org/10.1111/jcmm.13126
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