IGF2BP1-regulated expression of ERR[alpha] is involved in metabolic reprogramming of chemotherapy resistant osteosarcoma cells

Doxorubicin (Dox) is the standard treatment approach for osteosarcoma (OS), while acquired drug resistance seriously attenuates its treatment efficiency. The present study aimed to investigate the potential roles of metabolic reprogramming and the related regulatory mechanism in Dox-resistant OS cells. The results showed that the ATP levels, lactate generation, glucose consumption and oxygen consumption rate were significantly increased in Dox-resistant OS cells compared with parental cells. Furthermore, the results revealed that the increased expression of estrogen-related receptor alpha (ERR[alpha]) was involved in metabolic reprogramming in chemotherapy resistant OS cells, since targeted inhibition of ERR[alpha] restored the shifting of metabolic profiles. Mechanistic analysis indicated that the mRNA stability, rather than ERR[alpha] transcription was markedly increased in chemoresistant OS cells. Therefore, it was hypothesized that the 3?-untranslated region of ERR[alpha] mRNA was methylated by N.sup.6-methyladenine, which could further recruit insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress mRNA decay and increase mRNA stability. IGF2BP1 knockdown downregulated ERR[alpha] and reversed the metabolic alteration of resistant OS cells. Additionally, the oncogenic effect of the IGF2BP1/ERR[alpha] axis on Dox-resistant OS cells was verified by in vitro and in vivo experiments. Clinical analysis also revealed that the expression levels of IGF2BP1 and ERR[alpha] were associated with the clinical progression of OS. Collectively, the current study suggested that the IGF2BP1/ERR[alpha] axis could regulate metabolic reprogramming to contribute to the chemoresistance of OS cells. Keywords: Insulin-like growth factor 2 mRNA binding protein 1, Estrogen-related receptor alpha, Osteosarcoma, Doxorubicin, N.sup.6-methyladenine