Therapeutic Targeting of Myc-Reprogrammed Cancer Cell Metabolism

Abstract

Studies from many laboratories document that the MYC oncogene produces a pleiotropic transcription factor, Myc, which influences genes driven by all three RNA polymerases to orchestrate nutrient import with biomass accumulation for cell division. Myc has been shown to activate genes involved in glycolysis, glutaminolysis, and mitochondrial biogenesis to provide ATP and anabolic substrates for cell mass accumulation. Myc stimulates ribosome biogenesis and orchestrates the energetic demand for biomass accumulation through its regulation of glucose and glutamine import and metabolism. When normal cells are deprived of nutrients, endogenous MYC expression diminishes and cells withdraw from the cell cycle. However, ectopic MYC-driven cancer cells are locked in a state of deregulated biomass accumulation, which renders them addicted to glucose and glutamine. This addictive state can be exploited for cancer therapy, because nutrient deprivation kills Myc-driven cells and inhibition of the Myc targets, lactate dehydrogenase A or glutaminase, diminishes tumor xenograft growth in vivo.

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

“…Importantly, inhibitors of different complexes of the respiratory chain all induced a robust lipid accumulation. Our data hence strengthen the emerging evidence for a defined role of MYC in stimulating oxidative phosphorylation, which may contribute to fulfill the bio-energetic demands of cancer cells by coordinating mitochondrial energy metabolism with cell proliferation and survival (8,44).…”

“…Metabolic reprogramming is essential in cancer cells for adaptation to the tumor microenvironment and for maintenance of tumor growth (4,5). MYC is a potent regulator of these processes by inducing increased glycolysis and glutaminolysis (6,7) and by stimulating mitochondrial biogenesis and function (8)(9)(10). Several lines of experimental evidence support MYC as a therapeutic target (3,6,11,12).…”

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

“…However, given the inherent structure of MYC, it is difficult to design a small-molecule inhibitor that directly binds to MYC (32,33). Thus, we hypothesized that inhibiting downstream effector molecules such as ERRα would be an alternative method for suppressing MYC function.…”

Mammalian MYC Proteins and Cancer

“…Indeed, it can be argued that broadly effective strategies to treat or cure cancer cannot be realized until therapeutic means to attenuate MYC, or to take advantage of unique properties conferred by MYC on cancer cells, are developed. The topic of targeting MYC in cancer has gained considerable traction in recent years, and a number of excellent reviews have been written on this subject (e.g., [289][290][291][292]). Rather than extensively discussing this topic, therefore, we will instead describe some of the key observations that fuel the notion that MYC is a tractable target in cancer and highlight some strategies that are being pursued.…”