Contribution of branched chain amino acids to energy production and mevalonate synthesis in cancer cells

Abstract

Leucine, isoleucine and valine, known as branched chain amino acids (BCAAs), have been reported to be degraded by different cancer cells, and their biodegradation pathways have been suggested as anticancer targets. However, the mechanisms by which the degradation of BCAAs could support the growth of cancer cells remains unclear. In this work, ¹³C experiments have been carried out in order to elucidate the metabolic role of BCAA degradation in two breast cancer cell lines (MCF-7 and BCC). The results revealed that up to 36% of the energy production via respiration by MCF-7 cells was supported by the degradation of BCAAs. Also, 67% of the mevalonate (the precursor of cholesterol) synthesized by the cells was coming from the degradation of leucine. The results were lower for BCC cells (14 and 30%, respectively). The non-tumorigenic epythelial cell line MCF-10A was used as a control, showing that 10% of the mitochondrial acetyl-CoA comes from the degradation of BCAAs and no mevalonate production. Metabolic flux analysis around the mevalonate node, also revealed that significant amounts of acetoacetate are being produced from BCAA derived carbon, which could be at the source of lipid synthesis. From these results we can conclude that the degradation of BCAAs is an important energy and carbon source for the proliferation of some cancer cells and its therapeutic targeting could be an interesting option.

Keywords: Branched chain amino-acids; Cancer metabolism; Metabolic flux analysis.