Oncotarget

Priority Research Papers:

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

Huabo Wang, Lokendra Sharma, Jie Lu, Paul Finch, Steven Fletcher, Edward V. Prochownik _

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Oncotarget. 2015; 6:15857-15870. https://doi.org/10.18632/oncotarget.4327

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Abstract

Huabo Wang1, Lokendra Sharma1, Jie Lu1, Paul Finch1, Steven Fletcher2,3 and Edward V. Prochownik1,4,5

1 Division of Hematology/Oncology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh PA, USA

2 Department of Pharmaceutical Sciences, The University of Maryland School of Pharmacy, Baltimore, MD, USA

3 The Greenebaum Cancer Center, Baltimore MD, USA

4 Department of Microbiology and Molecular Genetics, The University of Pittsburgh, Pittsburgh, PA, USA

5 The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Correspondence to:

Edward V. Prochownik, email:

Keywords: 10058-F4, 10074-G5, JQ1, artemisinin, glycolysis

Received: March 31, 2015 Accepted: April 10, 2015 Published: May 30, 2015

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.


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