TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner

Abstract Background In the widespread adoption of chemotherapy, drug resistance has been the major obstacle to tumor elimination in cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma-associated chemoresistance. Methods We performed a cytotoxicity analysis of methotrexate (MTX)...

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Autores principales:	Yangbo Xu, Yafei Li, Xiaofan Chen, Feifan Xiang, Yong Deng, Zhong Li, Daiqing Wei
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	TGF-β Chemoresistance Succinate dehydrogenase Osteosarcoma Hypoxia-inducible factor 1α (HIF1α) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/5313b179f6de476981abfbc885072129
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spelling	oai:doaj.org-article:5313b179f6de476981abfbc8850721292021-11-14T12:30:26ZTGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner10.1186/s12885-021-08954-71471-2407https://doaj.org/article/5313b179f6de476981abfbc8850721292021-11-01T00:00:00Zhttps://doi.org/10.1186/s12885-021-08954-7https://doaj.org/toc/1471-2407Abstract Background In the widespread adoption of chemotherapy, drug resistance has been the major obstacle to tumor elimination in cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma-associated chemoresistance. Methods We performed a cytotoxicity analysis of methotrexate (MTX) and cisplatin (CIS) in TGF-β-treated osteosarcoma cells. Then, the metabolite profile of the core metabolic energy pathways in Saos-2 and MG-63 cell extracts was analyzed by 1H-NMR. We detected the expression of succinate dehydrogenase (SDH), STAT1, and hypoxia-inducible factor 1α (HIF1α) in TGF-β-treated osteosarcoma cells and further tested the effects of these molecules on the cytotoxicity induced by chemotherapeutic agents. Using in vivo experiments, we examined the tumor growth and survival time of Saos-2-bearing mice treated with a combination of chemotherapeutic agents and a HIF1α inhibitor. Results The metabolic analysis revealed enhanced succinate production in osteosarcoma cells after TGF-β treatment. We further found a decrease in SDH expression and an increase in HIF1α expression in TGF-β-treated osteosarcoma cells. Consistently, blockade of SDH efficiently enhanced the resistance of Saos-2 and MG-63 cells to MTX and CIS. Additionally, a HIF1α inhibitor significantly strengthened the anticancer efficacy of the chemotherapeutic drugs in mice with osteosarcoma cancer. Conclusion Our study demonstrated that TGF-β attenuated the expression of SDH by reducing the transcription factor STAT1. The reduction in SDH then caused the upregulation of HIF1α, thereby rerouting glucose metabolism and aggravating chemoresistance in osteosarcoma cells. Linking tumor cell metabolism to the formation of chemotherapy resistance, our study may guide the development of additional treatments for osteosarcoma.Yangbo XuYafei LiXiaofan ChenFeifan XiangYong DengZhong LiDaiqing WeiBMCarticleTGF-βChemoresistanceSuccinate dehydrogenaseOsteosarcomaHypoxia-inducible factor 1α (HIF1α)Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBMC Cancer, Vol 21, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TGF-β Chemoresistance Succinate dehydrogenase Osteosarcoma Hypoxia-inducible factor 1α (HIF1α) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	TGF-β Chemoresistance Succinate dehydrogenase Osteosarcoma Hypoxia-inducible factor 1α (HIF1α) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yangbo Xu Yafei Li Xiaofan Chen Feifan Xiang Yong Deng Zhong Li Daiqing Wei TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
description	Abstract Background In the widespread adoption of chemotherapy, drug resistance has been the major obstacle to tumor elimination in cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma-associated chemoresistance. Methods We performed a cytotoxicity analysis of methotrexate (MTX) and cisplatin (CIS) in TGF-β-treated osteosarcoma cells. Then, the metabolite profile of the core metabolic energy pathways in Saos-2 and MG-63 cell extracts was analyzed by 1H-NMR. We detected the expression of succinate dehydrogenase (SDH), STAT1, and hypoxia-inducible factor 1α (HIF1α) in TGF-β-treated osteosarcoma cells and further tested the effects of these molecules on the cytotoxicity induced by chemotherapeutic agents. Using in vivo experiments, we examined the tumor growth and survival time of Saos-2-bearing mice treated with a combination of chemotherapeutic agents and a HIF1α inhibitor. Results The metabolic analysis revealed enhanced succinate production in osteosarcoma cells after TGF-β treatment. We further found a decrease in SDH expression and an increase in HIF1α expression in TGF-β-treated osteosarcoma cells. Consistently, blockade of SDH efficiently enhanced the resistance of Saos-2 and MG-63 cells to MTX and CIS. Additionally, a HIF1α inhibitor significantly strengthened the anticancer efficacy of the chemotherapeutic drugs in mice with osteosarcoma cancer. Conclusion Our study demonstrated that TGF-β attenuated the expression of SDH by reducing the transcription factor STAT1. The reduction in SDH then caused the upregulation of HIF1α, thereby rerouting glucose metabolism and aggravating chemoresistance in osteosarcoma cells. Linking tumor cell metabolism to the formation of chemotherapy resistance, our study may guide the development of additional treatments for osteosarcoma.
format	article
author	Yangbo Xu Yafei Li Xiaofan Chen Feifan Xiang Yong Deng Zhong Li Daiqing Wei
author_facet	Yangbo Xu Yafei Li Xiaofan Chen Feifan Xiang Yong Deng Zhong Li Daiqing Wei
author_sort	Yangbo Xu
title	TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
title_short	TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
title_full	TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
title_fullStr	TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
title_full_unstemmed	TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
title_sort	tgf-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a sdh/hif1α dependent manner
publisher	BMC
publishDate	2021
url	https://doaj.org/article/5313b179f6de476981abfbc885072129
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TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner

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