TY - JOUR T1 - γ-Glutamylcysteine Synthetase Mediates the c-Myc-Dependent Response to Antineoplastic Agents in Melanoma Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1015 LP - 1023 DO - 10.1124/mol.107.038687 VL - 72 IS - 4 AU - Barbara Benassi AU - Gabriella Zupi AU - Annamaria Biroccio Y1 - 2007/10/01 UR - http://molpharm.aspetjournals.org/content/72/4/1015.abstract N2 - This study aims to investigate the role of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme for glutathione (GSH) synthesis, in the c-Myc-dependent response to antineoplastic agents. We found that specific c-Myc inhibition depleted cells of GSH by directly reducing the gene expression of both heavy and light subunits of the γ-GCS enzyme and increased their susceptibility to antineoplastic drugs with different mechanisms of action, such as cisplatin (CDDP), staurosporine (STR), and 5-fluorouracil (5-FU). The effect caused by c-Myc inhibition on CDDP and STR response, but not to 5-FU treatment, is directly linked to the impairment of the γ-GCS expression, because up-regulation of γ-GCS reverted drug sensitivity, whereas the interference of GSH synthesis increased drug susceptibility as much as after c-Myc down-regulation. The role of γ-GCS in the c-Myc-directed drug response depends on the capacity of drugs to trigger reactive oxygen species (ROS) production. Indeed, although 5-FU exposure did not induce any ROS, CDDP- and STR-induced oxidative stress enhanced the recruitment of c-Myc on both γ-GCS promoters, thus stimulating GSH neosynthesis and allowing cells to recover from ROS-induced drug damage. In conclusion, our data demonstrate that the γ-GCS gene is the downstream target of c-Myc oncoprotein, driving the response to ROS-inducing drugs. Thus, γ-GCS impairment might specifically sensitize high c-Myc tumor cells to chemotherapy. The American Society for Pharmacology and Experimental Therapeutics ER -