Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion

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.

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

“…However, MYC inhibition strategies have been developed based on interrupting protein–protein interactions with MAX to abolish MYC‐dependent transcriptional activity . As a proof of concept, we demonstrated that MYC inhibitors blocked FGF2‐induced cell proliferation in vitro in MCF‐7 and T47D cells, this inhibition occurred even at concentrations lower than those reported to block cell proliferation in other cell lines, underscoring the exquisite sensitivity of these models . For in vivo assays, we used the C4‐HI murine model in which we have already demonstrated that its hormone‐independent growth relies on stromal FGF2 .…”

Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

“…cancer cells or T cells) we find a transient increase in c-Myc following influenza infection (Figure 3E). c-Myc inhibitor a well-described direct inhibitor of c-Myc, also known as 10058-F4 (Calbiochem, Billerica MA), was used to determine if blocking c-Myc could restore normal metabolic phenotype (Hammoudeh et al, 2009; Rahl et al, 2010; Wang et al, 2015; Yin et al, 2003). Indeed, while the inhibitor alone increased bioenergetics, in the context of IAV infection c-Myc inhibitor reduced both ECAR and OCR to near normal levels in a dose dependent manner that were significantly lower than infection alone (Figure 3F–G).…”

Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo

“…It can promote cell proliferation, cell-cycle progression, survival and apoptosis resistance [46]. Several of these genes have been indentified, including cyclin D1, Bcl-2 and c-Myc [38,[47][48][49][50][51]. Our results show that BRD4 silencing by targeted shRNAs led to c-Myc downregulation in 786-O cells.…”