Stress eating and tuning out: Cancer cells re-wire metabolism to counter stress

Abstract

Cancer cells reprogram metabolism to maintain rapid proliferation under often stressful conditions. Glycolysis and glutaminolysis are two central pathways that fuel cancer metabolism. Allosteric regulation and metabolite driven post-translational modifications of key metabolic enzymes allow cancer cells glycolysis and glutaminolysis to respond to changes in nutrient availability and the tumor microenvironment. While increased aerobic glycolysis (the Warburg effect) has been a noted part of cancer metabolism for over 80 years, recent work has shown that the elevated levels of glycolytic intermediates are critical to cancer growth and metabolism due to their ability to feed into the anabolic pathways branching off glycolysis such as the pentose phosphate pathway and serine biosynthesis pathway. The key glycolytic enzymes phosphofructokinase-1 (PFK1), pyruvate kinase (PKM2) and phosphoglycerate mutase 1 (PGAM1) are regulated by upstream and downstream metabolites to balance glycolytic flux with flux through anabolic pathways. Glutamine regulation is tightly controlled by metabolic intermediates that allosterically inhibit and activate glutamate dehydrogenase, which fuels the tricarboxylic acid cycle by converting glutamine derived glutamate to α-ketoglutarate. The elucidation of these key allosteric regulatory hubs in cancer metabolism will be essential for understanding and predicting how cancer cells will respond to drugs that target metabolism. Additionally, identification of the structures involved in allosteric regulation will inform the design of anti-metabolism drugs which bypass the off-target effects of substrate mimics. Hence, this review aims to provide an overview of allosteric control of glycolysis and glutaminolysis.

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

“…First, they must synthesize or otherwise provide anabolic precursors to support their growth and proliferation (1,2). Second, they must generate sufficient amounts of ATP to drive the de novo synthesis or uptake of these precursors and their subsequent assembly into macromolecules (1,3).…”

Glutaminolysis and autophagy in cancer

“…121 However, the antitumor mechanism of EGCG has not been clearly related with its ability to inhibit GLUD1. 122 Another interesting option to decrease MTORC1 activity could be the inhibition of EGLNs, which links glutaminolysis with MTORC1 activation. Interestingly, several molecules able to inhibit EGLNs are currently being evaluated in clinical trials for the treatment of anemia (FG-2216, FG-4592, GSK1278863A, and AKB-6548).…”

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

“…The enzyme O-GlcNAc transferase (OGT) catalyzes the addition of the amino sugar to target proteins, whereas the enzyme O-GlcNAcase (OGA) catalyzes the removal of the sugar (5,6). Some substrates of O-GlcNAc are alternatively targeted by kinases (7)(8)(9). Thus, there is an extensive crosstalk between O-GlcNAc and pathways or mechanisms that are regulated by protein phosphorylation-signaling cascades (7)(8)(9).…”

“…Some substrates of O-GlcNAc are alternatively targeted by kinases (7)(8)(9). Thus, there is an extensive crosstalk between O-GlcNAc and pathways or mechanisms that are regulated by protein phosphorylation-signaling cascades (7)(8)(9).…”