TGF-β Suppressed Succinat Dehydrogenase to Promote Osteosarcoma Chemo-Resistance Through An HIF1α Dependent Manner

Abstract 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 1 H-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.