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Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation
Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient‐derived cells (PDCs), an...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9284171/ https://www.ncbi.nlm.nih.gov/pubmed/35187863 http://dx.doi.org/10.1002/advs.202103887 |
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author | Zhang, Hui‐Lu Chen, Ping Yan, He‐Xin Fu, Gong‐Bo Luo, Fei‐Fei Zhang, Jun Zhao, Shi‐Min Zhai, Bo Yu, Jiang‐Hong Chen, Lin Cui, Hao‐Shu Chen, Jian Huang, Shuai Zeng, Jun Xu, Wei Wang, Hong‐Yang Liu, Jie |
author_facet | Zhang, Hui‐Lu Chen, Ping Yan, He‐Xin Fu, Gong‐Bo Luo, Fei‐Fei Zhang, Jun Zhao, Shi‐Min Zhai, Bo Yu, Jiang‐Hong Chen, Lin Cui, Hao‐Shu Chen, Jian Huang, Shuai Zeng, Jun Xu, Wei Wang, Hong‐Yang Liu, Jie |
author_sort | Zhang, Hui‐Lu |
collection | PubMed |
description | Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient‐derived cells (PDCs), and cell lines, it is found that liver cancer cells display stem‐like characteristics upon glutamine shortage due to maintaining the stemness of tumor initiating cells (TICs) and even promoting transformation of non‐TICs into stem‐like cells by glutamine starvation. Increased expression of glutamine synthetase (GS) is essential for maintaining and promoting stem‐like characteristics of liver cancer cells during glutamine starvation. Mechanistically, glutamine starvation activates Rictor/mTORC2 to induce HDAC3‐mediated deacetylation and stabilization of GS. Rictor is significantly correlated with the expression of GS and stem marker OCT4 at tumor site, and closely correlates with poor prognosis of hepatocellular carcinomas. Inhibiting components of mTORC2‐HDAC3‐GS axis decrease TICs and promote xenografts regression upon glutamine‐starvation therapy. Collectively, the data provides novel insights into the role of Rictor/mTORC2‐HDAC3 in reprogramming glutamine metabolism to sustain stemness of cancer cells. Targeting Rictor/HDAC3 may enhance the efficacy of glutamine‐starvation therapy and limit the rapid growth and malignant progression of tumors. |
format | Online Article Text |
id | pubmed-9284171 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92841712022-07-15 Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation Zhang, Hui‐Lu Chen, Ping Yan, He‐Xin Fu, Gong‐Bo Luo, Fei‐Fei Zhang, Jun Zhao, Shi‐Min Zhai, Bo Yu, Jiang‐Hong Chen, Lin Cui, Hao‐Shu Chen, Jian Huang, Shuai Zeng, Jun Xu, Wei Wang, Hong‐Yang Liu, Jie Adv Sci (Weinh) Research Articles Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient‐derived cells (PDCs), and cell lines, it is found that liver cancer cells display stem‐like characteristics upon glutamine shortage due to maintaining the stemness of tumor initiating cells (TICs) and even promoting transformation of non‐TICs into stem‐like cells by glutamine starvation. Increased expression of glutamine synthetase (GS) is essential for maintaining and promoting stem‐like characteristics of liver cancer cells during glutamine starvation. Mechanistically, glutamine starvation activates Rictor/mTORC2 to induce HDAC3‐mediated deacetylation and stabilization of GS. Rictor is significantly correlated with the expression of GS and stem marker OCT4 at tumor site, and closely correlates with poor prognosis of hepatocellular carcinomas. Inhibiting components of mTORC2‐HDAC3‐GS axis decrease TICs and promote xenografts regression upon glutamine‐starvation therapy. Collectively, the data provides novel insights into the role of Rictor/mTORC2‐HDAC3 in reprogramming glutamine metabolism to sustain stemness of cancer cells. Targeting Rictor/HDAC3 may enhance the efficacy of glutamine‐starvation therapy and limit the rapid growth and malignant progression of tumors. John Wiley and Sons Inc. 2022-02-20 /pmc/articles/PMC9284171/ /pubmed/35187863 http://dx.doi.org/10.1002/advs.202103887 Text en © 2022 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Zhang, Hui‐Lu Chen, Ping Yan, He‐Xin Fu, Gong‐Bo Luo, Fei‐Fei Zhang, Jun Zhao, Shi‐Min Zhai, Bo Yu, Jiang‐Hong Chen, Lin Cui, Hao‐Shu Chen, Jian Huang, Shuai Zeng, Jun Xu, Wei Wang, Hong‐Yang Liu, Jie Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation |
title | Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation |
title_full | Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation |
title_fullStr | Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation |
title_full_unstemmed | Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation |
title_short | Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation |
title_sort | targeting mtorc2/hdac3 inhibits stemness of liver cancer cells against glutamine starvation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9284171/ https://www.ncbi.nlm.nih.gov/pubmed/35187863 http://dx.doi.org/10.1002/advs.202103887 |
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