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

Abstract

Branched-chain amino acid (BCAA) catabolism and high levels of enzymes in the BCAA metabolic pathway have recently been shown to be associated with cancer growth and survival. However, the precise roles of BCAA metabolism in cancer growth and survival remain largely unclear. Here, we found that BCAA metabolism has an important role in human pancreatic ductal adenocarcinoma (PDAC) growth by regulating lipogenesis. Compared with nontransformed human pancreatic ductal (HPDE) cells, PDAC cells exhibited significantly elevated BCAA uptake through solute carrier transporters, which were highly upregulated in pancreatic tumor tissues compared with normal tissues. Branched-chain amino-acid transaminase 2 (BCAT2) knockdown markedly impaired PDAC cell proliferation, but not HPDE cell proliferation, without significant alterations in glutamate or reactive oxygen species levels. Furthermore, PDAC cell proliferation, but not HPDE cell proliferation, was substantially inhibited upon knockdown of branched-chain α-keto acid dehydrogenase a (BCKDHA). Interestingly, BCKDHA knockdown had no significant effect on mitochondrial metabolism; that is, neither the level of tricarboxylic acid cycle intermediates nor the oxygen consumption rate was affected. However, BCKDHA knockdown significantly inhibited fatty-acid synthesis, indicating that PDAC cells may utilize BCAAs as a carbon source for fatty-acid biosynthesis. Overall, our findings show that the BCAA metabolic pathway may provide a novel therapeutic target for pancreatic cancer.

Multifaceted role of branched-chain amino acid metabolism in cancer

“…Knockdown of the E1α subunit of the BCKDH complex (BCKDHA) substantially inhibits PDAC cell proliferation in vitro and in mice [ 9 ]. Although BCKDHA knockdown has no significant impact on the levels of TCA cycle intermediates or oxygen consumption rate, but significantly impedes fatty acid synthesis in PDAC cells [ 9 ]. Whether or not BCAAs are used as the carbon source for the biosynthesis of fatty acids in PDAC remains to be investigated.…”

HSDL2 Acts as a Promoter in Pancreatic Cancer by Regulating Cell Proliferation and Lipid Metabolism

“… 16–18 Recently, Lee et al observed that branched-chain amino acids sustain metabolism and thus play a main role in pancreatic ductal adenocarcinoma (PDAC) growth by adjusting lipogenesis. 19 HSDL2 has received widespread attention for its possible involvement in lipid metabolism, and it is also well known as one of the major tumor markers when lipid metabolism is abnormal. However, the expression of HSDL2 in cell growth and lipid metabolism of PC remains unclear.…”

Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours

“…Our results provide evidence for dependency on the BCKDH complex and suggest its synergistic involvement with BCAT2 in regulating BCAA metabolism in PDAC cells. Recent studies investigated BCAT2’s role in PDAC development and found BCAT2 is elevated in PDAC models 42 , 43 . Our work develops further understanding of BCAA metabolism in the PDAC TME, especially in context of the pancreatic cancer-cell centric observations of previous studies.…”