c-Myc Metabolic Addiction in Cancers Counteracted by Resveratrol and NQO2

Abstract

Transcription factor c-myc is frequently amplified/overexpressed in human cancers. One event c-myc controls is metabolic reprogramming or the addiction for glucose and/or glutamine as nutrients. Rewiring of metabolic circuitry provides cancer cells with a gain-of-survival advan - tage. Accordingly, the aversion of two types of oncogenic-distinct metabolic addictions via c-myc control offers an anti-tumorigenic approach. Resveratrol reportedly inhibits the uptake/ transport of glucose or glutamine and reduces c-myc expression in cancer cells. Whether c-myc control by resveratrol involves quinone reductase NQO2 is unknown. NQO2 expressing (shRNA08) and knockdown (shRNA25) CWR22Rv1 prostate cancer cells were generated and used to study the role of NQO2 in growth and cell cycle control. Immunoblot analyses were used to evaluate the changes of cell cycle-associated proteins. NQO2 in mediating degradation of cyclin D1 via AKT/GSK-3β by resveratrol was tested by determining AKT and chymotryp - sin-like proteasome activities. Molecular modeling and pull-down/deletion assays were used to evaluate the interaction between NQO2 and AKT. Resveratrol interacts with NQO2, a qui - none reductase that plays a key role in resveratrol-induced AKT/GSK3β-mediated degradation of cyclin D1. In this chapter, we unravel control of expression and stability of c-myc by the res - veratrol-NQO2 axis as an approach to overcome c-myc-mediated metabolic reprogramming. that NQO2 NF-kB activation; NQO2 deletion potentiates the induction of apoptosis by abolishing TNF-induced cell survival kinases JNK, AKT, p38, and p44/p42 MAPK NQO2 C/EBPα proteasomes target dimeric NQO2 its other functions. novel pertain to c-myc T58 NQO2-knockdown cells, NQO2: AKT controls stability c-myc AKT/GSK3β-c-myc T-58 phosphorylation, by regulation of activity and functioning of the proteasome. Results of these studies will provide support for the as yet untested hypothesis regarding the indirect role of NQO2 in controlling AKT → GSK3β → c-myc T58 phosphorylation → c-myc degradation by proteasome, and the direct role of res veratrol acting as a metabolic switch to shut off c-myc-mediated metabolic reprogramming in cancer cells.