Simvastatin reprograms lipid metabolism in B16.F10 melanoma cells to favor an early resistant phenotype.

Our previous studies demonstrated that simvastatin (SIM) inhibited B16.F10 murine melanoma cell proliferation in vivo and in vitro via strong suppressing the production of subunit α of hypoxia inducible factor 1 (HIF-1) (HIF-1 α)-a key regulator of cancer cell adaptation to hypoxia. However, beyond its known role in hypoxia, normoxic expression of HIF-1α in melanoma has been linked to increased cancer cell aggressiveness, underscoring its broader impact on tumor biology. Since the translation of HIF-1α is modulated by Akt, SIM effects on both regulatory factors in relation to cancer cell metabolism under normoxia were investigated. SIM- induced metabolic changes were analyzed at mRNA and at protein level. Our data suggested that SIM reprogrammed glucose metabolism to ensure replenishment of the tricarboxylic acid (TCA) cycle, favoring its biosynthetic role over its energy role. This shift supported lipid-derived signaling molecules synthesis including isoprenoids and prostaglandins, favoring traits associated with cell survival and drug tolerance. Additional validation in human A375 melanoma cells demonstrated comparable antiproliferative effects of SIM, while in silico cross-species transcriptomic analysis revealed shared suppression of cell-cycle-related programs together with context-dependent metabolic responses. Our results have important clinical implications, as they emphasize the potential of targeting key lipid metabolic pathways to overcome the adaptive mechanisms associated with normoxic HIF-1α expression. Thus, our data offer promise for novel combination therapies which disrupt the metabolic plasticity of melanoma, to ultimately improve therapeutic outcomes.