Revisiting the Warburg Effect with Focus on Lactate

SIMPLE SUMMARY: Almost a century ago, Nobel Prize laureate Otto Warburg realized that cancer cells consumed much more glucose than normal cells and also produced large amounts of lactate even in aerobic conditions, which was very surprising at the time. After decades of research, it eventually became clear that lactate was much more than just a waste product and that cancer cells were programmed to use it to their advantage. In this review, we discuss the current state of knowledge regarding the purpose of lactate in cancer and how our understanding of its significance has evolved over time. ABSTRACT: Rewired metabolism is acknowledged as one of the drivers of tumor growth. As a result, aerobic glycolysis, or the Warburg effect, is a feature of many cancers. Increased glucose uptake and glycolysis provide intermediates for anabolic reactions necessary for cancer cell proliferation while contributing sufficient energy. However, the accompanying increased lactate production, seemingly wasting glucose carbon, was originally explained only by the need to regenerate NAD(+) for successive rounds of glycolysis by the lactate dehydrogenase (LDH) reaction in the cytosol. After the discovery of a mitochondrial LDH isoform, lactate oxidation entered the picture, and lactate was recognized as an important oxidative fuel. It has also been revealed that lactate serves a variety of signaling functions and helps cells adapt to the new environment. Here, we discuss recent findings on lactate metabolism and signaling in cancer while attempting to explain why the Warburg effect is adopted by cancer cells.