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BMC Cancer

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Open Access 01-12-2021 | osteosarcoma | Research

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

Authors: Yangbo Xu, Yafei Li, Xiaofan Chen, Feifan Xiang, Yong Deng, Zhong Li, Daiqing Wei

Published in: BMC Cancer | Issue 1/2021

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.

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Title: TGF-β protects osteosarcoma cells from chemotherapeutic cytotoxicity in a SDH/HIF1α dependent manner
Authors: Yangbo Xu
Yafei Li
Xiaofan Chen
Feifan Xiang
Yong Deng
Zhong Li
Daiqing Wei
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: osteosarcoma
Methotrexate
Methotrexate
Osteosarcoma
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08954-7

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Abstract

Background

Methods

Results

Conclusion

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