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.
Highlights
Pancreatic cancer is a highly aggressive tumor with a poor prognosis[1]
Pancreatic ductal adenocarcinoma (PDAC) cells display increased Branched-chain amino acid (BCAA) uptake As the role of BCAAs in tumor growth is complex and depends on the tumor type, we explored the importance of BCAAs in PDAC growth
Given that several solute carrier (SLC) transporters (Slc1a5, Slc3a2, and Slc7a5) are known to mediate BCAA transport[23,24,25], we speculate that the expression of these SLC transporters might be elevated in PDAC cells
Summary
Pancreatic cancer is a highly aggressive tumor with a poor prognosis[1]. Pancreatic ductal adenocarcinoma (PDAC) is the most common malignant pancreatic tumor, with an expected 5-year survival rate of ~8%2. Compared with the levels in nonproliferating normal cells, the robust increases in the uptake of glucose and the production of lactate in cancer cells, known as the Warburg effect[5], constitute the first hallmarks of cancer. Compared with normal differentiated cells, cancer cells have considerably different metabolic requirements that enable them to continuously grow. Cancer cells must have altered metabolic pathways to obtain sufficient amounts of the metabolites required for high rates of proliferation[6]. Oncogene activation and/or epigenetic alterations drive changes in metabolism that support cell proliferation and survival under nutrient-replete conditions[7]. Targeting the considerable metabolic differences between cancer cells and normal cells holds promise as an ideal strategy for cancer therapy[8]. Many studies have reported that abnormal levels of lipids are critical for the unlimited proliferation and the metastasis
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