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

Benassi, Barbara; Zupi, Gabriella; Biroccio, Annamaria

doi:10.1124/mol.107.038687

Cited by 13 publications

(13 citation statements)

References 35 publications

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“…Moreover, miR-34b/c-mediated c-Myc stimulation is set upstream the GSH neo-synthesis, as both miR mimic administration and Myc silencing in LNCaP-USP2a WT cells are responsible for γ -GCS inhibition and consequent GSH depletion, with further chemo-sensitization to pro-oxidant agents. This is consistent with our previously reported data demonstrating a direct antioxidant role of c-Myc through regulation of glutathione synthesis, 34, 39 also corroborated by Gao et al who disclosed c-Myc involvement in energy and reactive oxygen species homeostasis. 57 These data might strengthen the hypothesis of a therapeutic approach in USP2a-overexpressing prostate lesions based on the combination of conventional chemotherapy with either miR synthetic drugs or siMyc.…”

Section: Discussionsupporting

confidence: 93%

“…We previously demonstrated that c-Myc transcription factor regulates the γ -glutamyl-cysteine synthetase ( γ -GCS), the rate-limiting enzyme catalyzing GSH biosynthesis, by directly binding and activating the promoters of both heavy ( γ -GCS H ) and light ( γ -GCS L ) subunits. 34, 39 We therefore verified whether the GSH modulation may proceed via a Myc-dependent regulation of γ -GCS expression in our USP2a WT prostate experimental model. As reported in Supplementary Figure 6, USP2a WT stimulates both γ -GCS subunit expression in LNCaP cells, in terms of mRNA, protein, and enzyme activity rise.…”

Section: Resultssupporting

confidence: 56%

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USP2a alters chemotherapeutic response by modulating redox

Benassi

Marani²,

Loda

et al. 2013

Cell Death Dis

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Cancer cells are characterized by altered ubiquitination of many proteins. The ubiquitin-specific protease 2a (USP2a) is a deubiquitinating enzyme overexpressed in prostate adenocarcinomas, where it exhibits oncogenic behavior in a variety of ways including targeting c-Myc via the miR-34b/c cluster. Here we demonstrate that USP2a induces drug resistance in both immortalized and transformed prostate cells. Specifically, it confers resistance to typically pro-oxidant agents, such as cisplatin (CDDP) and doxorubicin (Doxo), and to taxanes. USP2a overexpression protects from drug-induced oxidative stress by reducing reactive oxygen species (ROS) production and stabilizing the mitochondrial membrane potential (ΔΨ), thus impairing downstream p38 activation and triggering of apoptosis. The molecular mediator of the USP2a protective function is the glutathione (GSH). Through miR-34b/c-driven c-Myc regulation, USP2a increases intracellular GSH content, thus interfering with the oxidative cascade triggered by chemotherapeutic agents. In light of these findings, targeting Myc and/or miR-34b/c might revert chemo-resistance.

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 56%

USP2a alters chemotherapeutic response by modulating redox

Benassi

Marani²,

Loda

et al. 2013

Cell Death Dis

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“…This dual role of c-Myc as a transcriptional factor involved in signaling depends upon the absence or presence of growth factors, over-expression of c-Myc (as in MEF cells), and differences in cell models. c-Myc has been reported to both increase ROS generation and participate in the induction of antioxidant enzymes (12-14). These pleiotropic effects of c-Myc are due to the large number of genes under its control (5).…”

Section: Discussionmentioning

confidence: 99%

“…Functional c-Myc binding consensus sites were identified on both GCL subunits promoters (13). Exposure to H 2 O 2 enhances c-Myc recruitment to GCL regulatory regions through an ERK-dependent pathway (13,14). …”

Section: Introductionmentioning

confidence: 99%

C‐Myc is a Nrf2‐interacting protein that negatively regulates phase II genes through their electrophile responsive elements

2010

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Summaryc-Myc is a transcription factor that is implicated in many cellular processes including proliferation, apoptosis and cancers. Recently, c-Myc was shown to be involved in regulation of glutamate cysteine ligase through E-box sequences. This investigation examined whether c-Myc also regulates phase II genes through interaction with the electrophile response element (EpRE). Experiments were conducted in human bronchial epithelial cells using si-RNA to knock down c-Myc. RT-PCR and reporter assays were used to measure transcription and promoter activity. c-Myc downregulated transcription and promoter activity of phase II genes.

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“…Additionally, the bi-functional genes LIAS and TRAP1 would also participate in the reduction of ROS generated from the mitochondria. We expected to observe an increase in genes involved in glutathione metabolism, based on recent data 40 but neither of the glutamine-cysteine ligase (GCL) subunits were increased above our threshold. It is possible that the increased generation of ROS in myc -/-cells (Fig.…”

Section: Discussionmentioning

confidence: 99%