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-Glutamylcysteine Synthetase Mediates the c-Myc-Dependent Response to Antineoplastic Agents in Melanoma Cells

Experimental Chemotherapy Laboratory, Experimental Research Center, Regina Elena Cancer Institute, Rome, Italy

This study aims to investigate the role of -glutamylcysteine synthetase (-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 -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 -GCS expression, because up-regulation of -GCS reverted drug sensitivity, whereas the interference of GSH synthesis increased drug susceptibility as much as after c-Myc down-regulation. The role of -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 -GCS promoters, thus stimulating GSH neosynthesis and allowing cells to recover from ROS-induced drug damage. In conclusion, our data demonstrate that the -GCS gene is the downstream target of c-Myc oncoprotein, driving the response to ROS-inducing drugs. Thus, -GCS impairment might specifically sensitize high c-Myc tumor cells to chemotherapy.

Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Experimental Research Center, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. E-mail: biroccio{at}ifo.it