WHEN CANCER CELLS GO TO THE WARBURG EFFECT, WHERE DOES LACTATE GO? EXPLORING LACTATE METABOLISM IN CANCER CELLS
Vu, Kha Hoai Bao
Vu, Kha Hoai Bao
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2025-05-19
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Abstract
Metabolic reprogramming is a hallmark of cancer, allowing tumor cells to sustain proliferation under varying nutrient and oxygen conditions. One of the most well-known adaptations is the Warburg effect, wherein cancer cells preferentially utilize glycolysis to generate ATP and produce lactate, even in the presence of oxygen. While lactate has long been considered a metabolic waste product, emerging studies suggest that it may have regulatory functions beyond energy production. In this study, we investigate how lactate influences the metabolic enzyme malate dehydrogenase 1 (MDH1), a key component of the malate-aspartate shuttle and a contributor to cytosolic NAD+ regeneration. Using CRISPR-mediated MDH1 knockout models, cell proliferation assays, a cell-free mitochondrial system, and direct enzymatic activity measurements, we demonstrate that lactate--both L- and D-enantiomers--activates MDH1. This activation is independent of lactate's conventional metabolic conversion via lactate dehydrogenase. Notably, D-lactate, which mammalian cells cannot metabolize, produced similar effects to L-lactate, indicating a non-metabolic, potentially signaling-based mechanism. Structural modeling using AlphaFold2 further supports the presence of a putative lactate-binding site on MDH1. These findings suggest a novel paradigm in which lactate directly regulates mitochondrial metabolism, redefining its role in the Warburg effect and its contribution to cancer cell proliferation.