Glycolysis in Tumorigenesis: Mechanisms and Therapeutic Implications

Dear Colleagues,

Most of the energy used by the cellular machinery is generated in the form of ATP molecules. ATP can be produced by two metabolic pathways: glycolysis, with the production of two ATP molecules/glucose molecule; oxidative metabolism (tricarboxylic acid cycle and oxidative phosphorylation), producing approximately 36 ATP molecules/glucose molecule. Under aerobic conditions, cells rely on oxidative metabolism for energy production, while switching to the much less efficient glucose fermentation under hypoxic conditions (Chandel NS 2021). In fact, oxidative metabolism has been shown to generate >90 % of ATP in aerobic conditions.

Glycolysis, however, may become the predominant energy-producing pathway in tumors, even under aerobic conditions. This occurs in response to several stimuli, such as hypoxia, oncogenes, mechanical stress and other stimuli from the tumor microenvironment, which upregulate the expression of glycolytic enzymes and glycolysis overall.

Glycolysis discharges two main tasks in tumors: first, its conventional functions, i.e., the delivery of energy and precursors for biomass production. In addition, upregulated glycolytic enzymes may acquire new, unconventional functions, referred to as “moonlighting functions”: these include the induction of mutations and other tumor-initiating events, increased expression of oncoproteins, bypassing of senescence, induction of antiapoptotic effects and drug resistance. These effects lead to a variety of different activities with tumor-promoting effects: instigation of tumor initiation, stimulation of tumor cell proliferation, induction of epithelial–mesenchymal transition, autophagy and metastasis, immunosuppressive effects.

The acquisition of these “moonlighting functions” is very intriguing. In fact, glycolysis is a very ancient form of energy production that is highly conserved in living organisms. For this reason, it is highly unlikely that moonlighting functions have evolved before the acquisition of the capacity to produce energy. Rather, it appears more likely that these functions have been acquired during subsequent phases of evolution, perhaps because of the cytoplasmic location of the glycolytic machinery and its connection to other metabolic and signaling pathways, making glycolysis optimally suited to respond to cell-autonomous or non-autonomous stressors.

Clarification and understanding of these effects and the role of glycolysis in tumor initiation and progression may allow us to gain new insights into tumor pathogenesis and offer new perspectives for the identification of innovative therapeutic approaches that may complement the currently available armamentarium against cancer.

Chandel NS. Glycolysis. Cold Spring Harb. Perspect. Biol. 2021, 13(5), a040535. doi: 10.1101/cshperspect.a040535.

Dr. Fabrizio Marcucci
Dr. Shibo Wei
Dr. Marco Cordani
Guest Editors

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