Abstract
The c-Myc (Myc) oncoprotein is deregulated in a large proportion of diverse human cancers. Considerable effort has therefore been directed at identifying pharmacologic inhibitors as potential anti-neoplastic agents. Three such groups of small molecule inhibitors have been described. The first is comprised of so-called "direct" inhibitors, which perturb Myc's ability to form productive DNA-binding heterodimers in association with its partner, Max. The second group is comprised of indirect inhibitors, which largely function by targeting the BET-domain protein BRD4 to prevent the proper formation of transcriptional complexes that assemble in response to Myc-Max DNA binding. Thirdly, synthetic lethal inhibitors cause the selective apoptosis of Myc over-expressing either by promoting mitotic catastrophe or altering Myc protein stability. We report here a common mechanism by which all Myc inhibitors, irrespective of class, lead to eventual cellular demise. This involves the depletion of ATP stores due to mitochondrial dysfunction and the eventual down-regulation of Myc protein. The accompanying metabolic de-regulation causes neutral lipid accumulation, cell cycle arrest, and an attempt to rectify the ATP deficit by up-regulating AMP-activated protein kinase (AMPK). These responses are ultimately futile due to the lack of functional Myc to support the requisite anabolic response. Finally, the effects of Myc depletion on ATP levels, cell cycle arrest, differentiation and AMPK activation can be mimicked by pharmacologic inhibition of the mitochondrial electron transport chain without affecting Myc levels. Thus, all Myc inhibitors promote a global energy collapse that appears to underlie many of their phenotypic consequences.
Highlights
C-Myc (Myc) is among the most frequently deregulated oncoproteins encountered in human cancers and is a well-studied cause of numerous experimental cancers [1,2,3]
Other types of synthetic lethal inhibitors include compounds targeting CDK1 and Aurora B kinases, which are required for the proper assembly and function of the mitotic spindle [26, 27] and derivatives of the anti-malarial compound artemisinin, which presumably de-stabilize Myc by increasing rather than inhibiting GSK3β and promoting more efficient Myc protein degradation in tumors whose survival is highly Myc-dependent [28]
An additional direct small molecule inhibitor with a mechanism of action distinct from that of 10058-F4 and 10074-G5 and their analogs was the recently described JKY-2169, a proteomimetic, that was designed to interact with Myc only in its α−helical conformation that it assumes upon dimerizing with Max [17, 44]
Summary
C-Myc (Myc) is among the most frequently deregulated oncoproteins encountered in human cancers and is a well-studied cause of numerous experimental cancers [1,2,3]. Considerable effort has been directed at identifying small molecule inhibitors of Myc or selective downstream Myc target gene products that are necessary to confer or maintain the transformed phenotype [4,5,6,7] The importance of this goal is underscored by the fact that Myc is required for the proliferation and/or survival of many cancers even when it is not obviously deregulated [8, 9]. Other types of synthetic lethal inhibitors include compounds targeting CDK1 and Aurora B kinases, which are required for the proper assembly and function of the mitotic spindle [26, 27] and derivatives of the anti-malarial compound artemisinin, which presumably de-stabilize Myc by increasing rather than inhibiting GSK3β and promoting more efficient Myc protein degradation in tumors whose survival is highly Myc-dependent [28]. Myc’s tendency to promote aneuploidy [13, 29] by compromising the transformed cell’s ability to faithfully partition its abnormal chromosome complement
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