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PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor
The existence of cancer stem cells (CSCs) accounts for hepatocellular carcinoma (HCC) treatment resistance, relapse, and metastasis. Although the elimination of cancer stem cells is crucial for cancer treatment, strategies for their elimination are limited. Here, we report that a remarkable increase...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280510/ https://www.ncbi.nlm.nih.gov/pubmed/32513919 http://dx.doi.org/10.1038/s41419-020-2631-9 |
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author | Liu, Fengchao Wu, Xiaoling Qian, Yanzhi Jiang, Xin Wang, Yiying Gao, Jian |
author_facet | Liu, Fengchao Wu, Xiaoling Qian, Yanzhi Jiang, Xin Wang, Yiying Gao, Jian |
author_sort | Liu, Fengchao |
collection | PubMed |
description | The existence of cancer stem cells (CSCs) accounts for hepatocellular carcinoma (HCC) treatment resistance, relapse, and metastasis. Although the elimination of cancer stem cells is crucial for cancer treatment, strategies for their elimination are limited. Here, we report that a remarkable increase in PIK3C3 was detected in HCC tissues and liver CSCs. Upregulated PIK3C3 facilitated liver CSC expansion in HCC cells; RNA interference-mediated silencing of PIK3C3 had an opposite effect. Furthermore, PIK3C3 inhibition by inhibitors effectively eliminated liver CSCs and inhibited the growth of tumors in vivo. The phosphoinositide 3-kinase (PI3K) pathway is considered an important hallmark of cancer. One of our recent studies found that prolonged inhibition by inhibitors of class I PI3K induces liver CSCs expansion. To our surprise, PIK3C3 inhibition blocked the expansion of CSCs induced by PI3K inhibitor; moreover, treatment with the combination of PIK3C3 inhibitor and PI3K inhibitor in maximal suppresses the expansion of liver CSCs of tumors in mice. Mechanistically, inhibition of PIK3C3 inhibit the activation of SGK3, a CSCs promoter, induced by PI3K inhibitor. We also show that PIK3C3 inhibitor suppresses liver CSCs by activation of the AMP-activated kinase (AMPK). Although PIK3C3 plays a critical role in autophagy, we find that PIK3C3 regulates liver CSCs independent of the autophagy process. These findings uncover the effective suppression of liver CSCs by targeting PIK3C3, and targeting PIK3C3 in combination with PI3K inhibitor inhibits the expansion of liver CSCs efficiently, which is an attractive therapeutic regimen for the treatment of HCC. |
format | Online Article Text |
id | pubmed-7280510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-72805102020-06-16 PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor Liu, Fengchao Wu, Xiaoling Qian, Yanzhi Jiang, Xin Wang, Yiying Gao, Jian Cell Death Dis Article The existence of cancer stem cells (CSCs) accounts for hepatocellular carcinoma (HCC) treatment resistance, relapse, and metastasis. Although the elimination of cancer stem cells is crucial for cancer treatment, strategies for their elimination are limited. Here, we report that a remarkable increase in PIK3C3 was detected in HCC tissues and liver CSCs. Upregulated PIK3C3 facilitated liver CSC expansion in HCC cells; RNA interference-mediated silencing of PIK3C3 had an opposite effect. Furthermore, PIK3C3 inhibition by inhibitors effectively eliminated liver CSCs and inhibited the growth of tumors in vivo. The phosphoinositide 3-kinase (PI3K) pathway is considered an important hallmark of cancer. One of our recent studies found that prolonged inhibition by inhibitors of class I PI3K induces liver CSCs expansion. To our surprise, PIK3C3 inhibition blocked the expansion of CSCs induced by PI3K inhibitor; moreover, treatment with the combination of PIK3C3 inhibitor and PI3K inhibitor in maximal suppresses the expansion of liver CSCs of tumors in mice. Mechanistically, inhibition of PIK3C3 inhibit the activation of SGK3, a CSCs promoter, induced by PI3K inhibitor. We also show that PIK3C3 inhibitor suppresses liver CSCs by activation of the AMP-activated kinase (AMPK). Although PIK3C3 plays a critical role in autophagy, we find that PIK3C3 regulates liver CSCs independent of the autophagy process. These findings uncover the effective suppression of liver CSCs by targeting PIK3C3, and targeting PIK3C3 in combination with PI3K inhibitor inhibits the expansion of liver CSCs efficiently, which is an attractive therapeutic regimen for the treatment of HCC. Nature Publishing Group UK 2020-06-08 /pmc/articles/PMC7280510/ /pubmed/32513919 http://dx.doi.org/10.1038/s41419-020-2631-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Liu, Fengchao Wu, Xiaoling Qian, Yanzhi Jiang, Xin Wang, Yiying Gao, Jian PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor |
title | PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor |
title_full | PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor |
title_fullStr | PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor |
title_full_unstemmed | PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor |
title_short | PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor |
title_sort | pik3c3 regulates the expansion of liver cscs and pik3c3 inhibition counteracts liver cancer stem cell activity induced by pi3k inhibitor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280510/ https://www.ncbi.nlm.nih.gov/pubmed/32513919 http://dx.doi.org/10.1038/s41419-020-2631-9 |
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