Novel Anticancer Therapy Targets Tumors' Glycolytic Metabolism

Most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria like most normal cells. Malignant, rapidly growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.

Investigators at the Whitehead Institute for Biomedical Research (Cambridge, MA, USA) performed a genome-wide haploid genetic screen to identify genes that became active when cancer cells were exposed to 3-BrPA.They reported in the December 2, 2012, online edition of the journal Nature Genetics that they had identified the SLC16A1 (solute carrier family 16, member 1) gene product, MCT1 (monocarboxylic acid transporter 1), as the main determinant of 3-BrPA sensitivity. MCT1 is a proton-linked monocarboxylate transporter that catalyzes the movement of many monocarboxylates, such as lactate and pyruvate, across the plasma membrane.

MCT1 was necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels were the best predictor of 3-BrPA sensitivity and were most elevated in glycolytic cancer cells. Forced MCT1 expression in 3-BrPA–resistant cancer cells sensitized tumor xenografts to 3-BrPA treatment in vivo.

"Our work suggests a different strategy for cancer therapy that takes advantage of the capacity of a cancer cell to take up something toxic that a normal cell does not," said senior author Dr. David Sabatini, professor of biology at the Whitehead Institute for Biomedical Research. "As a result, that toxic molecule would kill the cancer cell. By identifying transporters on the surface of cancer cells, you might be able to find a molecule that a specific transporter would carry into the cell, and that molecule would be toxic to that cell. You really could have something that is much more selective to cancer cells."

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Whitehead Institute for Biomedical Research