Abstract
Fermentative glycolysis, an ancient evolved metabolic pathway, is exploited by rapidly growing tissues and tumors but also occurs in response to the nutritional and energetic demands of differentiated tissues. The lactic acid it produces is transported across cell membranes through reversible H+/lactate−symporters (MCT1 and MCT4) and is recycled in organs as a major metabolic precursor of gluconeogenesis and an energy source. Concentrations of lactate in the tumor environment, investigated utilizing an induced metabolic bioluminescence imaging (imBI) technique, appear to be dominant biomarkers of tumor response to irradiation and resistance to treatment. Suppression of lactic acid formation by genetic disruption of lactate dehydrogenases A and B in aggressive tumors reactivated OXPHOS (oxidative phosphorylation) to maintain xenograft tumor growth at a halved rate. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Furthermore, the global reduction of tumor acidity contributes to activation of the antitumor immune responses, offering hope for future clinical applications.
Highlights
A century has passed since Otto Warburg discovered that animal tumors produced large amounts of lactate
The preference that rapidly growing tumors have for glucose fermentation, a lowATP-producing pathway, in contrast to respiration, has been paradoxical, and yet this metabolic choice is almost universal for rapid proliferation as long as nutrients and glucose are provided (Vander Heiden et al 2009)
As reported lactic acid is transported in and out of tumor cells via reversible monocarboxylate transporters (MCTs), which are expressed in virtually all cells (Halestrap 2012), and plays a major role in tumor progression
Summary
A century has passed since Otto Warburg discovered that animal tumors produced large amounts of lactate. His experiments were performed in vitro with excised pieces of tumors and showed that fermentation (anaerobic glucose breakdown to lactate) was preferred for growth rather than respiration (oxidative glucose breakdown) present in normal cells (Warburg 1923, Warburg et al 1927). Okamoto and Warburg (Warburg et al 1927) reported that a few hours of suppression of oxygen and glucose was sufficient to kill tumor cells. These pioneering observations a century ago illuminated the two complementary bioenergetics pathways of respiration and fermentation. In 1856, lactate was rediscovered by Louis Pasteur from the Gram-positive, facultative anaerobe Lactobacillus
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