Archive | 2021
TGF-β Suppressed Succinat Dehydrogenase to Promote Osteosarcoma Chemo-Resistance Through An HIF1α Dependent Manner
Abstract
\n Background:Despite the widespread adoption of chemotherapy, drug resistance has been the major obstacle in tumor elimination of cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma chemo-resistance. Methods:We performed cytotoxicity analysis of methotrexate (MTX) and cisplatin (CIS) in TGF-β treated osteosarcoma cells. Then a metabolite profile of the core energetic routes was analyzed by 1H-NMR in Saos-2 and MG-63 cell extracts. 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 of chemotherapeutic agents. In vivo, we examined the tumor growth and survival time of Saos-2 bearing mice given the combination therapy of chemotherapeutic agents and a HIF1α inhibitor. Results:Metabolic analysis revealed an enhanced succinate production of osteosarcoma cells after TGF-β treatment. We further found the decrease in SDH expression and the increase in HIF1α expression of TGF-β treated osteosarcoma cells. Consistently, blockade of SDH aggravated the resistance of Saos-2/MG-63 cells to MTX and CIS. Also, a HIF1α inhibitor significantly strengthened the anti-cancer efficacy of chemotherapeutic drugs in mice with osteosarcoma cancer.Conclusion:Our study demonstrated that TGF-β attenuated the expression of SDH through reducing the transcription factor STAT1. The reduction of SDH then caused the up-regulation of HIF1α, thereby rerouting the glucose metabolism and aggravating chemo-resistance in osteosarcoma cells. Linking tumor cell metabolism to the formation of chemotherapy resistance, our study may guide the development of more effective treatments of osteosarcoma.