Molecular Pathways: Targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer

Abstract

MYC is a multifunctional transcription factor that is deregulated in many human cancers. MYC impacts a collaborative genetic program that orchestrates cell proliferation, metabolism, and stress responses. Although the progression of MYC-amplified tumors shows robust dependence on MYC activity, directly targeting MYC as a therapeutic method has proven to be technically difficult. Therefore, alternative approaches are currently under development with a focus on interference with MYC-mediated downstream effects. To fuel rapid cell growth, MYC reprograms cancer cell metabolism in a way that is substantially different from normal cells. The MYC-induced metabolic signature is characterized by enhanced glucose and glutamine uptake, increased lactate production, and altered amino acid metabolism. Targeting MYC-reprogrammed cancer cell metabolism is considered to be promising based on multiple preclinical studies. In addition, the increased biosynthetic demand of MYC-driven tumors coupled with limited nutrient access within tumor microenvironments create multiple levels of oncogenic stress, which can also be used as tumor-specific targets for pharmacologic intervention. Presumably, the best therapeutic strategy for treating MYC-amplified tumors is combined targeting of multiple MYC-mediated pathways, especially those involved in regulating cell proliferation, metabolism, and oncogenic stress.

Figure 1

The pleiotropic transcription factor MYC reprograms cancer cell metabolism to fuel rapid cell growth. MYC increases glycolytic flux by inducing the expression of glucose transporter GLUT1 and glycolytic enzyme LDH. MYC in cooperation with HIF increases PDK expression to inhibit PDH and prevents central carbon metabolites from entering the TCA cycle (the Warburg effect). Glutaminolysis is stimulated upon activation of several glutamine transporters (ASCT2, SN2, etc.) and GLS in MYC-amplified cells. MYC is also capable of enhancing serine, glycine, and proline metabolism by modulating several related enzymes, including PHGDH, SHMT, POX, P5CS, and PYCR1. In addition to MYC’s role in metabolic regulation, MYC activation results in multiple cellular responses mediating oncogenic stress that is often present in rapidly-growing cancer cells, such as the UPR and apoptosis. The MYC-regulated downstream targets/effects that facilitate cancer progression are highlighted in , while those antagonizing MYC-induced tumorigenesis are highlighted in . A number of compounds that directly target MYC or downstream pathways emanating from MYC are also highlighted in . GLUT1, glucose transporter 1; 3-PG, 3-phosphoglycerate; LDH, lactate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; ASCT2, also known as solute carrier family 1, member 5 (SLC1A5); SN2, also known as solute carrier family 38, member 5 (SLC38A5); GLS, glutaminase; GDH, glutamate dehydrogenase; PHGDH, phosphoglycerate dehydrogenase; SHMT, serine hydroxymethyltransferase; POX, proline oxidase, also known as proline dehydrogenase (PRODH); P5C, pyrroline-5-carboxylate; GSA, glutamic gamma-semialdehyde; P5CS, P5C synthase; PYCR1, P5C reductase 1; HIF, hypoxia inducible factor; UPR, unfolded protein response; FRT, fenretinide, also known as 4-hydroxyphenyl retinamide (4-HPR); EGCG, epigallocatechin gallate; AOA, aminooxyacetate. DON, 6-diazo-5-oxo-L-norleucine; DCA, dichloroacetate.