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Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma

One contributor to the high mortality of osteosarcoma is its reduced sensitivity to chemotherapy, but the mechanism involved is unclear. Improving the sensitivity of osteosarcoma to chemotherapy is urgently needed to improve patient survival. We found that chemotherapy triggered apoptosis of human o...

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Autores principales: Tang, Zhen, Wei, Xinghui, Li, Tian, Wang, Wei, Wu, Hao, Dong, Hui, Liu, Yichao, Wei, Feilong, Shi, Lei, Li, Xiaokang, Guo, Zheng, Xiao, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502982/
https://www.ncbi.nlm.nih.gov/pubmed/34646824
http://dx.doi.org/10.3389/fcell.2021.722960
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author Tang, Zhen
Wei, Xinghui
Li, Tian
Wang, Wei
Wu, Hao
Dong, Hui
Liu, Yichao
Wei, Feilong
Shi, Lei
Li, Xiaokang
Guo, Zheng
Xiao, Xin
author_facet Tang, Zhen
Wei, Xinghui
Li, Tian
Wang, Wei
Wu, Hao
Dong, Hui
Liu, Yichao
Wei, Feilong
Shi, Lei
Li, Xiaokang
Guo, Zheng
Xiao, Xin
author_sort Tang, Zhen
collection PubMed
description One contributor to the high mortality of osteosarcoma is its reduced sensitivity to chemotherapy, but the mechanism involved is unclear. Improving the sensitivity of osteosarcoma to chemotherapy is urgently needed to improve patient survival. We found that chemotherapy triggered apoptosis of human osteosarcoma cells in vitro and in vivo; this was accompanied by increased Sestrin2 expression. Importantly, autophagy was also enhanced with increased Sestrin2 expression. Based on this observation, we explored the potential role of Sestrin2 in autophagy of osteosarcoma. We found that Sestrin2 inhibited osteosarcoma cell apoptosis by promoting autophagy via inhibition of endoplasmic reticulum stress, and this process is closely related to the PERK-eIF2α-CHOP pathway. In addition, our study showed that low Sestrin2 expression can effectively reduce autophagy of human osteosarcoma cells after chemotherapy, increase p-mTOR expression, decrease Bcl-2 expression, promote osteosarcoma cell apoptosis, and slow down tumour progression in NU/NU mice. Sestrin2 activates autophagy by inhibiting mTOR via the PERK-eIF2α-CHOP pathway and inhibits apoptosis via Bcl-2. Therefore, our results explain one underlying mechanism of increasing the sensitivity of osteosarcoma to chemotherapy and suggest that Sestrin2 is a promising gene target.
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spelling pubmed-85029822021-10-12 Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma Tang, Zhen Wei, Xinghui Li, Tian Wang, Wei Wu, Hao Dong, Hui Liu, Yichao Wei, Feilong Shi, Lei Li, Xiaokang Guo, Zheng Xiao, Xin Front Cell Dev Biol Cell and Developmental Biology One contributor to the high mortality of osteosarcoma is its reduced sensitivity to chemotherapy, but the mechanism involved is unclear. Improving the sensitivity of osteosarcoma to chemotherapy is urgently needed to improve patient survival. We found that chemotherapy triggered apoptosis of human osteosarcoma cells in vitro and in vivo; this was accompanied by increased Sestrin2 expression. Importantly, autophagy was also enhanced with increased Sestrin2 expression. Based on this observation, we explored the potential role of Sestrin2 in autophagy of osteosarcoma. We found that Sestrin2 inhibited osteosarcoma cell apoptosis by promoting autophagy via inhibition of endoplasmic reticulum stress, and this process is closely related to the PERK-eIF2α-CHOP pathway. In addition, our study showed that low Sestrin2 expression can effectively reduce autophagy of human osteosarcoma cells after chemotherapy, increase p-mTOR expression, decrease Bcl-2 expression, promote osteosarcoma cell apoptosis, and slow down tumour progression in NU/NU mice. Sestrin2 activates autophagy by inhibiting mTOR via the PERK-eIF2α-CHOP pathway and inhibits apoptosis via Bcl-2. Therefore, our results explain one underlying mechanism of increasing the sensitivity of osteosarcoma to chemotherapy and suggest that Sestrin2 is a promising gene target. Frontiers Media S.A. 2021-09-27 /pmc/articles/PMC8502982/ /pubmed/34646824 http://dx.doi.org/10.3389/fcell.2021.722960 Text en Copyright © 2021 Tang, Wei, Li, Wang, Wu, Dong, Liu, Wei, Shi, Li, Guo and Xiao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Tang, Zhen
Wei, Xinghui
Li, Tian
Wang, Wei
Wu, Hao
Dong, Hui
Liu, Yichao
Wei, Feilong
Shi, Lei
Li, Xiaokang
Guo, Zheng
Xiao, Xin
Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma
title Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma
title_full Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma
title_fullStr Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma
title_full_unstemmed Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma
title_short Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma
title_sort sestrin2-mediated autophagy contributes to drug resistance via endoplasmic reticulum stress in human osteosarcoma
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502982/
https://www.ncbi.nlm.nih.gov/pubmed/34646824
http://dx.doi.org/10.3389/fcell.2021.722960
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