D-mannose suppresses HIF-1α mediated metabolic reprogramming in clear cell renal cell carcinoma

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Abstract
The inactivation mutation of VHL drives the progression of clear cell renal cell carcinoma (ccRCC), while the deletion of VHL leads to the failure of HIF-1/2α to degrade normally through the ubiquitin proteasome pathway. Notably, the abnormal accumulation of HIF-1/2α results in metabolic reprogramming and promotes the occurrence of tumors. Therefore, inhibition of metabolic reprogramming of ccRCC may be an effective treatment. In methodology, the viabilities of tumor cells were detected by cell counting kit-8 assay in vitro. The expression levels of related proteins were analyzed by western blotting assay, and the mRNA levels of genes were assessed by RT-qPCR assay. Glucose uptake, intracellular lactate and NADPH production were measured according to relevant instructions. Here, we found that D-mannose inhibits the proliferation of ccRCC in vitro. Mechanistically, D-mannose suppresses the transcription of HIF-1α downstream target genes, including GLUT1, LDHA, PDK1 and VEGF, by downregulating the protein level of HIF-1α in ccRCC cells. Furthermore, D-mannose reduces glucose uptake and intracellular lactate and NADPH production. To sum up, this study demonstrates that targeting HIF-1α by D-mannose to inhibit metabolic reprogramming is a promising strategy for ccRCC and complements a previously unknown role of D-mannose in cancer treatment.

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