{'fraction_non_alphanumeric': 0.0233655358346439, 'fraction_numerical': 0.008312738710402157, 'mean_word_length': 5.442836468885673, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
MYC‐induced sensitivity of human malignant melanoma to proteasome inhibitors – a KaMYCaze effect

Development of selective, targetspecific and potent antitumor therapy has always been a Holy Grail of cancer researchers. This Holy Grail has justified numerous research ventures aimed at identification of tumor-specific molecular process or characteristics that can be exploited to improve the therapeutic margin by killing malignant rather than normal cells. This direction of efforts reached its first major peak of success upon development of Gleevec that targets the BCR-Abl oncogene that is absent of normal cells. Remarkably, a major success was scored by a type of drug whose design seems to be as non-specific as one could imagine: the inhibitors of proteasomes, the multiprotein enzymatic complex that governs ubiquitination-dependent degradation of numerous proteins. Whereas function of proteasomes is essential for diverse physiologic processes that occur in normal cell (including regulation of DNA replication and repair, cell cycle, gene expression, enzymatic activity, etc), several proteasomal inhibitors such as Bortezomib have demonstrated potent antitumorigenic properties while being unexpectedly tolerable for normal ⁄ benign tissues. Naturally, many research groups began investigating the mechanisms by which Bortezomib and other proteasome inhibitors kill tumor cells. These studies are important not only for optimization of Bortezomib treatment targets and regimens, and its combination with other agents, but also for dealing with resistance of tumors to these agents that inevitably arises in treated patients. While these mechanisms of killing are incredibly complex, dysregulation of survival signals, particularly involving NFjB, induction of a lethal endoplasmic reticulum-associated unfolded protein response (also termed ER stress) and activation of the apoptotic machinery are among the usual suspects. What are the underlying reasons for an exquisite sensitivity of tumor cells to Bortezomib-induced killing? The recent paper by Nikiforov et al. (2007) shed the light on why melanoma cells are highly sensitive to Bortezomib whereas normal melanocytes are not. This study stemmed from the observation by M. Soengas group and others that programmed cell death induced by proteasome inhibitors in melanoma cells requires a tumor cell-specific upregulation of a proapoptotic protein Noxa (Fernandez et al., 2005). The M. Soengas and M. Nikiforov groups joined forces to delineate the underlying mechanism. They demonstrated that the induction of NOXA by bortezomib occurs via transactivation of its gene expression in a manner that is directly dependent on the interaction of oncogenic protein and transcription factor, c-MYC, with conserved MYC-binding sites found at the NOXA gene promoter. Further experiments using modulation of c-MYC levels (including either its overexpression or knockdown) validated the elevated levels of c-MYC (often found in numerous human malignancies including melanomas) as a pivotal determinant of cell sensitivity to Bortezomib-induced accumulation of Noxa and ensuing efficient cytotoxicity of this proteasome inhibitor. Normal melanocytes that harbor a lesser levels ⁄ activity of MYC display conversely lesser sensitivity to proteasome inhibitor. While providing a remarkable mechanistic insight, this paper yet raised a number of important questions that remain to be answered. One is the role of another notorious NOXA inducer – p53 tumor suppressor protein whose role in Bortezomibdriven induction of Noxa in melanoma cells was not critical (Nikiforov et al., 2007). Other studies, while also suggesting that proteasome inhibitors could be highly effective as a monotherapy against Myc-induced lymphomas, also showed that p53 status is an important determinant of sensitivity of these tumors to proteasome inhibitors (Yu et al., 2007). Another intriguing issue is a contribution of other c-MYC targets to the bortezomib toxicity, which is not completely abolished upon experimental inhibition of Noxa. Regardless of solving these and other puzzles, Nikiforov et al. have reported on a compelling and elegant study that brings our attention to c-MYC whose role in melanoma development is surprisingly poorly Coverage on: Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition Nikiforov, M.A., et al., Proc. Natl Acad. Sci. USA 104: 19488–19493, 2007.