The discrepancy in sensitivity to metformin between the two cell types could be linked to the differential expression of HIF-1α despite that both cell lines were reported to carry a wild-type VHL. Furthermore, we highlighted here that antineoplastic effects of metformin against ccRCC are, at least partly, based on its ability to activate AMPK and the subsequent inhibition of Akt/mTOR axis in addition to a focal effect on the inhibition of the Wnt/β-catenin pathway. Here, VHL is linked to nonpapillary renal cell carcinoma.