The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues

Abstract

That cancer cells show patterns of metabolism different from normal cells has been known for over 50 years. Yet, it is only in the past decade or so that an appreciation of the benefits of these changes has begun to emerge. Altered cancer cell metabolism was initially attributed to defective mitochondria. However, we now realize that most cancers do not have mitochondrial mutations and that normal cells can transiently adopt cancer-like metabolism during periods of rapid proliferation. Indeed, an encompassing, albeit somewhat simplified, conceptual framework to explain both normal and cancer cell metabolism rests on several simple premises. First, the metabolic pathways used by cancer cells and their normal counterparts are the same. Second, normal quiescent cells use their metabolic pathways and the energy they generate largely to maintain cellular health and organelle turnover and, in some cases, to provide secreted products necessary for the survival of the intact organism. By contrast, undifferentiated cancer cells minimize the latter functions and devote their energy to producing the anabolic substrates necessary to maintain high rates of unremitting cellular proliferation. Third, as a result of the uncontrolled proliferation of cancer cells, a larger fraction of the metabolic intermediates normally used by quiescent cells purely as a source of energy are instead channeled into competing proliferation-focused and energy-consuming anabolic pathways. Fourth, cancer cell clones with the most plastic and rapidly adaptable metabolism will eventually outcompete their less well-adapted brethren during tumor progression and evolution. This attribute becomes increasingly important as tumors grow and as their individual cells compete in a constantly changing and inimical environment marked by nutrient, oxygen, and growth factor deficits. Here, we review some of the metabolic pathways whose importance has gained center stage for tumor growth, particularly those under the control of the c-Myc (Myc) oncoprotein. We discuss how these pathways differ functionally between quiescent and proliferating normal cells, how they are kidnapped and corrupted during the course of transformation, and consider potential therapeutic strategies that take advantage of common features of neoplastic and metabolic disorders.

Myc‐dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor‐2

“…pY1212 creates a binding site for growth factor receptor-bound protein 2 (GRB2) and the regulatory p85 subunit of phosphoinositide 3 0 -kinase (PI3Kp85), mediating activation of ERK1/2 and Akt pathways, respectively. ERK1/2 and Akt pathways positively and negatively regulate the expression of c-Myc [20,21], a transcription factor that controls expression of a broad set of genes involved in cell cycle progression, cell proliferation, apoptosis, and cell metabolism [20,22]. We show that pY1212 is required for VEGFR2-dependent EC proliferation in a c-Myc-dependent manner and that the temporal establishment of the Vegfr2 Y1212F/Y1212F vascular phenotype differs between C57Bl/6 and FVB mouse strains.…”

Dynamic metabolic reprogramming in dendritic cells: an early response to influenza infection that is essential for effector function

“…Indeed, decoupling of glycolysis and TCA cycle in cancers was once presumed to be a mitochondrial defect but is now postulated to produce a more robust and flexible metabolic program [43, 101]. c-Myc is considered a master regulator of cancer metabolism, and metabolic reprogramming by c-Myc is thought to allow cancer and activated immune cells to sustain supplies of anabolic building blocks while generating energy for their assembly[14, 63, 64, 68, 72]. Our data supports applying this idea to IAV-infected DC, given we found c-MYC expression increased in response to IAV infection and c-Myc inhibition significantly reduced glycolysis, respiration, and glutamine import, while preventing IAV-induced DC migration and induction of CD25+ and CD44+ CD8 T cells (Figs 4, 5A-F, and S5E Fig).…”

“…Thus, glutamine metabolism has the added benefit of increasing proton buffering capacity and cellular redox homeostasis including glutathione synthesis from glutaminase enzymes [71, 110] and when glutaminolysis is inhibited ROS increases [111]. Meanwhile, the first step of the TCA cycle is sensitive to ROS [64, 112–114] as is the respiratory chain and membrane permeability, and this mitochondrial damage potentiates ROS [115, 116]. Hence, it is conceivable that glutamine oxidation may have important advantages for an activated innate immune cell that produces ROS in conjunction with other effector functions that require high anabolism and energy production.…”

The metabolic response to inflammation in astrocytes is regulated by nuclear factor‐kappa B signaling

“…In other cell types, NF-κB signaling is implicated in the regulation of cellular metabolism (Goetzman & Prochownik, 2018; F I G U R E 6 Glucose transporter glucose transporter 1 (GLUT1) expression in mouse primary astrocytes was reduced after 24 hr treatment with lipopolysaccharide (LPS). Figure S2d; p = .95).…”