Copper deprivation modulates CTR1 and CUP1 expression and enhances cisplatin cytotoxicity in Saccharomyces cerevisiae

Saccharomyces cerevisiae has been established as a model system for cancer studies, due to the widely conserved family of genes involved in cell cycle progression, proliferation and apoptosis. In the current study, we sought to determine whether copper deprivation modulates sensitivity of yeast to cisplatin. Yeast cultures grown in low copper medium and exposed to bathocuproiene disulfate (BCS) resulted in significant reduction of intracellular copper. We report here that low copper medium rendered BY4741 hypersensitive to cisplatin (CDDP). Yeast grown in low copper medium exhibited ～2.0 fold enhanced cytotoxicity in survival and colony-forming ability, compared to copper adequate control cells grown in YPD. The effect of copper restriction on CDDP sensitivity appeared to be associated with the up regulation of CTR1, facilitating enhanced uptake and accumulation of CDDP. Also, CDDP further lowered copper deprivation-induced changes in CUP1 metallothionein levels, SOD activity and GSH levels. These changes were associated with increased protein oxidation and lipid peroxidation induced by CDDP. These results thus suggest that cisplatin cytotoxicity is potentiated under low copper conditions due to enhanced uptake and accumulation of cisplatin and also in part due to lowered antioxidant defense and increased oxidative stress imposed by copper deprivation.