γ-Glutamylcysteine synthetase mediates the c-Myc-dependent response to antineoplastic agents in melanoma cells

Barbara Benassi, Gabriella Zupi, Annamaria Biroccio

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 ROSinduced 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.

Original languageEnglish
Pages (from-to)1015-1023
Number of pages9
JournalMolecular Pharmacology
Volume72
Issue number4
DOIs
Publication statusPublished - Oct 2007

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Glutamate-Cysteine Ligase
Antineoplastic Agents
Melanoma
Staurosporine
Fluorouracil
Pharmaceutical Preparations
Reactive Oxygen Species
Oncogene Proteins
Enzymes
Cisplatin
Glutathione
Oxidative Stress
Up-Regulation
Down-Regulation
Gene Expression
Light
Drug Therapy
Genes
Neoplasms

ASJC Scopus subject areas

  • Pharmacology

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γ-Glutamylcysteine synthetase mediates the c-Myc-dependent response to antineoplastic agents in melanoma cells. / Benassi, Barbara; Zupi, Gabriella; Biroccio, Annamaria.

In: Molecular Pharmacology, Vol. 72, No. 4, 10.2007, p. 1015-1023.

Research output: Contribution to journalArticle

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