The Glycolytic Switch in Tumors: How Many Players Are Involved?

Abstract

Reprogramming of cellular metabolism is a hallmark of cancers. Cancer cells more readily use glycolysis, an inefficient metabolic pathway for energy metabolism, even when sufficient oxygen is available. This reliance on aerobic glycolysis is called the Warburg effect, and promotes tumorigenesis and malignancy progression. The mechanisms of the glycolytic shift in tumors are not fully understood. Growing evidence demonstrates that many signal molecules, including oncogenes and tumor suppressors, are involved in the process, but how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. Here, we summarize the current information on several main mediators and discuss their possible mechanisms for triggering the Warburg effect.

Keywords: aerobic glycolysis; glycolytic switch.; reprogramming of glucose metabolism; the Warburg effect; tumor metabolism.

Figure 1

Main steps in glycolysis and possible key enzymes regulated in the Warburg effect. The three reactions catalyzed by hexokinase (HK), phosphofructokinase-1 (PFK1), and pyruvate kinase (PK) in this process are rate-limiting steps. During glycolysis, four molecules of ATP are produced per molecule of oxidized glucose via substrate-level phosphorylation, and the net yield is two molecules of ATP after deduction of two ATPs consumed in phosphorylation. The fate of pyruvate depends largely on the availability of oxygen for the cells. Pyruvate is reduced to lactate under hypoxia via an anaerobic glycolysis pathway or, under aerobic conditions, oxidized to yield acetyl-coenzyme A, which is then oxidized completely to CO₂ via the citric acid cycle, resulting in the production of large amounts of ATP. G-6-P, glucose-6-phosphate; G6DP, glucose-6-phosphate dehydrogenase; GLUT, glucose transporter; Fru-2,6-P2, fructose-2,6-bisphosphate; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; TPI, triose phosphate isomerase.

Figure 2

HIF-1α is a master regulator of the Warburg effect and plays a critical role as an activator of aerobic glycolysis. Hypoxia increases the production of ROS, which stabilizes HIF-1α. HIF-1α induces expression of glucose transporters and glycolytic enzymes, facilitating glycolysis that is, in turn, essential for maintaining HIF-1α activity. Many oncogenes and tumor suppressors are involved in the regulation of HIF-1α. EZH2, enhancer of zeste 2 polycomb repressive complex 2; GRIM-19, gene associated with retinoid-interferon-induced mortality-19; LSD1, lysine specific demethylase 1; ROS, reactive oxygen species; RPS7, ribosomal protein S7; TKTL1, transkelolase-like 1; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; WWOX, WW domain-containing oxidoreductase.

Figure 3

The RTKs-PI3K-Akt-mTOR signal pathway plays an important role in the regulation of aerobic glycolysis. Akt and mTOR are central activators of the Warburg effect, promoting the expression of glucose transporters and glycolytic enzymes, which is regulated by many signal molecules. AMPK, adenosine monophosphate activated protein kinase; MUC16, mucin 16; mTOR, mammalian target of rapamycin; RTKs, receptor tyrosine kinases; Skp2, S-phase kinase-associated protein 2; TSC1/TSC2, tuberous sclerosis protein 1 and 2 complex.

Figure 4

Non-coding RNAs target glucose transporters and glycolytic enzymes. The downregulation of several miRNAs in some tumors facilitates aerobic glycolysis and promotes the development and progression of the tumors. HIF-1α is a primary target of non-coding RNAs. miRNA absence, or lncRNA-mediated HIF-1α stabilization, enhances HIF-1α activity, contributing to the Warburg effect. PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase.