Genes and Cancer Group

Spain

Genes and Cancer Group

Spain
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Martinez-Poveda B.,University of Malaga | Rodriguez-Nieto S.,Genes and Cancer Group | Garcia-Caballero M.,University of Malaga | Medina M.-A.,University of Malaga | And 3 more authors.
Marine Drugs | Year: 2012

Abstract: Aeroplysinin-1 is a brominated metabolite extracted from the marine sponge Aplysina aerophoba that has been previously characterized by our group as a potent antiangiogenic compound in vitro and in vivo. In this work, we provide evidence of a selective induction of apoptosis by aeroplysinin-1 in endothelial cells. Studies on the nuclear morphology of treated cells revealed that aeroplysinin-1 induces chromatin condensation and nuclear fragmentation, and it increases the percentage of cells with sub-diploid DNA content in endothelial, but not in HCT-116, human colon carcinoma and HT-1080 human fibrosarcoma cells. Treatment of endothelial cells with aeroplysinin-1 induces activation of caspases-2, -3, -8 and -9, as well as the cleavage of apoptotic substrates, such as poly (ADP-ribose) polymerase and lamin-A in a caspase-dependent mechanism. Our data indicate a relevant role of the mitochondria in the apoptogenic activity of this compound. The observation that aeroplysinin-1 prevents the phosphorylation of Bad relates to the mitochondria-mediated induction of apoptosis by this compound. © 2012 by the authors; licensee MDPI.


Romero O.A.,Genes and Cancer Group | Torres-Diz M.,Genes and Cancer Group | Pros E.,Genes and Cancer Group | Savola S.,MRC Holland | And 10 more authors.
Cancer Discovery | Year: 2014

Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, ampli-fication of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. SIGNIFICANCE: We discovered that the MYC-associated factor X gene, MAX, is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-deficient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-deficient tumors. © 2013 American Association for Cancer Research.

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