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Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk

OBJECTIVES: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial‐lysosomal crosstalk...

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Autores principales: Sheng, Jiyao, Shen, Luyan, Sun, Liankun, Zhang, Xuewen, Cui, Ranji, Wang, Lizhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536453/
https://www.ncbi.nlm.nih.gov/pubmed/31033054
http://dx.doi.org/10.1111/cpr.12609
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author Sheng, Jiyao
Shen, Luyan
Sun, Liankun
Zhang, Xuewen
Cui, Ranji
Wang, Lizhong
author_facet Sheng, Jiyao
Shen, Luyan
Sun, Liankun
Zhang, Xuewen
Cui, Ranji
Wang, Lizhong
author_sort Sheng, Jiyao
collection PubMed
description OBJECTIVES: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial‐lysosomal crosstalk in the cisplatin resistance of HCC cells. MATERIALS AND METHODS: Huh7 and HepG2 cells were subjected to different treatments. Flow cytometry was conducted to detect mitochondrial reactive oxygen species, mitochondrial mass, lysosomal function, mitochondrial membrane potential and apoptosis. Western blotting was performed to evaluate protein levels. The oxygen consumption rate was measured to evaluate mitochondrial function. RESULTS: Cisplatin activated mitophagy and lysosomal biogenesis, resulting in crosstalk between mitochondria and lysosomes and cisplatin resistance in HCC cells. Furthermore, a combination of cisplatin with the phosphatidylinositol‐3‐kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor PKI‐402 induced lysosomal membrane permeabilization. This effect changed the role of the lysosome from a protective one to that of a cell death promoter, completely destroying the mitochondrial‐lysosomal crosstalk and significantly enhancing the sensitivity of HCC cells to cisplatin. CONCLUSIONS: This is the first evidence of the importance of mitochondrial‐lysosomal crosstalk in the cisplatin resistance of HCC cells and of the destruction of this crosstalk by a PI3K/mTOR inhibitor to increase the sensitivity of HCC cells to cisplatin. This mechanism could be developed as a novel target for treatment of HCC in the future.
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spelling pubmed-65364532020-03-13 Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk Sheng, Jiyao Shen, Luyan Sun, Liankun Zhang, Xuewen Cui, Ranji Wang, Lizhong Cell Prolif Original Articles OBJECTIVES: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial‐lysosomal crosstalk in the cisplatin resistance of HCC cells. MATERIALS AND METHODS: Huh7 and HepG2 cells were subjected to different treatments. Flow cytometry was conducted to detect mitochondrial reactive oxygen species, mitochondrial mass, lysosomal function, mitochondrial membrane potential and apoptosis. Western blotting was performed to evaluate protein levels. The oxygen consumption rate was measured to evaluate mitochondrial function. RESULTS: Cisplatin activated mitophagy and lysosomal biogenesis, resulting in crosstalk between mitochondria and lysosomes and cisplatin resistance in HCC cells. Furthermore, a combination of cisplatin with the phosphatidylinositol‐3‐kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor PKI‐402 induced lysosomal membrane permeabilization. This effect changed the role of the lysosome from a protective one to that of a cell death promoter, completely destroying the mitochondrial‐lysosomal crosstalk and significantly enhancing the sensitivity of HCC cells to cisplatin. CONCLUSIONS: This is the first evidence of the importance of mitochondrial‐lysosomal crosstalk in the cisplatin resistance of HCC cells and of the destruction of this crosstalk by a PI3K/mTOR inhibitor to increase the sensitivity of HCC cells to cisplatin. This mechanism could be developed as a novel target for treatment of HCC in the future. John Wiley and Sons Inc. 2019-04-29 /pmc/articles/PMC6536453/ /pubmed/31033054 http://dx.doi.org/10.1111/cpr.12609 Text en © 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd This is an open access article under the terms of the 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
Sheng, Jiyao
Shen, Luyan
Sun, Liankun
Zhang, Xuewen
Cui, Ranji
Wang, Lizhong
Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
title Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
title_full Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
title_fullStr Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
title_full_unstemmed Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
title_short Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
title_sort inhibition of pi3k/mtor increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536453/
https://www.ncbi.nlm.nih.gov/pubmed/31033054
http://dx.doi.org/10.1111/cpr.12609
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