Branched-chain amino acids sustains pancreatic cancer growth by regulating lipid metabolism

Abstract

Branched-chain amino acids (BCAAs) catabolism and high levels of enzymes in the BCAAs pathway have recently been linked to cancer growth and survival. However, the specific roles of BCAAs metabolism in cancer growth and survival remains unclear. Here, I find that BCAAs metabolism plays an important role in the growth of human pancreatic duct adenocarcinoma (PDAC) through regulation of lipogenesis. PDAC cells exhibited significantly increased uptake of BCAAs through upregulated Branched-chain amino acid aminotransferase 2 (BCAT2) levels compared to non-transformed human pancreatic ductal cells (HPDEs). Knockdown of BCAT2 dramatically impaired PDAC growth without significant changes in glutamate and ROS levels, but did not impair HDPE growth. Furthermore, PDAC growth was strongly inhibited upon Branched-chain α-keto acid dehydrogenase a (BCKDHA) knockdown. Surprisingly, BCKDHA knockdown had no significant effect on mitochondrial metabolism, including tricarboxylic acid (TCA) cycle intermediates and oxygen consumption rate, but significantly reduced fatty acid synthesis, indicating that PDAC can supply carbon fuel to fatty acids using BCAAs. Thus, our data shows that BCAAs pathway may provide novel therapeutic targets for pancreatic cancer treatment.