C-Myc to Melanoma Cells: Drop Dead?

Abstract

Because the proteasome regulates the cell cycle and apoptosis, proteasome inhibitor-mediated tumor cell death is not that surprising. What is puzzling, however, given the vital role of the proteasome in protein turnover, is the paucity of side effects on normal cells. What makes protease inhibitors so tumor cell-selective? One such compound, bortezomib, increases the abundance, in cancer cells but not in normal cells, of the mRNA and protein of the proapoptotic factor, NOXA. Nikiforov et al . investigated the mechanism by which bortezomib causes cell death in melanoma cell lines. Western blotting analysis showed that the bortezomib-dependent increase in NOXA abundance in melanoma cells was blocked by the transcriptional inhibitor actinomysin D. Bortezomib still increased the abundance of NOXA in cell lines that were treated with short interfering RNAs specific for those transcription factors known to target NOXA : p53, hypoxia-inducible factor-1α (HIF-1α), and E2F-1. Computational analysis of the sequences surrounding the NOXA promoter revealed the presence of four putative binding sites for the oncoprotein c-Myc. Chromatin immunoprecipitation assays confirmed the binding of c-Myc to the NOXA promoter, whose abundance was increased, compared with control cells, after treatment with bortezomib. Knockdown of c-Myc in melanoma cells blocked the bortezomib-dependent increase in NOXA abundance, whereas overexpression of c-Myc in normal melanocytes increased the abundance of NOXA mRNA, which was further enhanced by bortezomib treatment. Overexpression of c-Myc in melanoma cells sensitized them to the effects of bortezomib, whereas knockdown of NOXA inhibited bortezomib-induced cell death. Together, these data suggest the unusual involvement of c-Myc in promoting apoptosis and provide a possible mechanism for the tumor cell-specific effect of proteasome inhibitors. M. A. Nikiforov, M. Riblett, W.-H. Tang, V. Gratchouck, D. Zhuang, Y. Fernandez, M. Verhaegen, S. Varambally, A. M. Chinnaiyan, A. J. Jakubowiak, M. S. Soengas, Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc. Natl. Acad. Sci. U.S.A. 104 , 19488-19493 (2007). [Abstract] [Full Text]