MYC-Induced Cancer Cell Energy Metabolism and Therapeutic Opportunities

Abstract

Although cancers have altered glucose metabolism, termed the Warburg effect, which describes the increased uptake and conversion of glucose to lactate by cancer cells under adequate oxygen tension, changes in the metabolism of glutamine and fatty acid have also been documented. The MYC oncogene, which contributes to the genesis of many human cancers, encodes a transcription factor c-Myc, which links altered cellular metabolism to tumorigenesis. c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism. With E2F1, c-Myc induces genes involved in nucleotide metabolism and DNA replication, and microRNAs that homeostatically attenuate E2F1 expression. With the hypoxia inducible transcription factor HIF-1, ectopic c-Myc cooperatively induces a transcriptional program for hypoxic adaptation. Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA), or indirectly, such as repression of microRNAs miR-23a/b to increase glutaminase (GLS) protein expression and glutamine metabolism. Ectopic MYC expression in cancers, therefore, could concurrently drive aerobic glycolysis and/or oxidative phosphorylation to provide sufficient energy and anabolic substrates for cell growth and proliferation in the context of the tumor microenvironment. Collectively, these studies indicate that Myc-mediated altered cancer cell energy metabolism could be translated for the development of new anticancer therapies. (Clin Cancer Res 2009;15(21):6479-83)

Cancer as a Metabolic Disease

“…The RTG response will activate MYC, Ras, HIF-1α, Akt, and mTor etc, which are required to facilitate and to sustain up-regulation of substrate level phosphorylation [61,110,113,167,168]. In addition to facilitating the uptake and metabolism of alternative energy substrates through substrate level phosphorylation, MYC and Ras further stimulate cell proliferation [136,169,170]. Part of this mechanism also includes inactivation of pRB, the function of which is dependent on mitochondrial activities and the cellular redox state [144].…”

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…As a result, the activated oncogenic network stimulates the initiation and development of TME by multiple reactions. ( , protein-protein interaction previously reported; the thickness of the blue line is qualitatively proportional to the reliability of the data) cancer-metabolism-related genes, oncogenes, and HIF1A triggers genesis of the TME [13,[47][48][49][50].…”

“…Furthermore, tumor cells produce large quantities of secreted lactate, which causes an acidic environment to stimulate reprogramming gene expression and the genesis of TME [8,[45][46][47][48][49][50][51][52][53][54][55][56][57]. Key genes responsible for abnormal cancer metabolism, such as DGLC and several other aerobic metabolic enzymes, can be targeted using their pharmacological inhibitors in glucose, glutamine, and fatty acid metabolic pathways.…”

L’effet Warburg

“…Parmi ces gènes, on trouve la LDHA, le transporteur de glucose GLUT1, Hk2, la phosphofructokinase et l'énolase 1 (ENO1) [19]. Par ailleurs, Myc induit la dégradation de la glutamine en stimulant l'expression de la glutaminase, qui transforme la glutamine en glutamate.…”