BCKDK alters the metabolism of non-small cell lung cancer

Abstract

Background: Metabolic reprogramming is a major feature of many tumors including non-small cell lung cancer (NSCLC). Branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in diabetes, obesity, and other diseases. However, the function of BCKDK in NSCLC is unclear. This study aimed to explore the function of BCKDK in NSCLC.Methods: Metabolites in the serum of patients with NSCLC and the supernatant of NSCLC cell cultures were detected using nuclear magnetic resonance (NMR) spectroscopy. Colony formation, cell proliferation, and cell apoptosis were assessed to investigate the function of BCKDK in the progression of NSCLC.Glucose uptake, lactate production, cellular oxygen consumption rate, extracellular acidification rate, and reactive oxygen species (ROS) were measured to examine the function of BCKDK in glucose metabolism.The expression of BCKDK was measured using reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemical assay.Results: Compared with healthy controls and postoperative NSCLC patients, increased branched-chain amino acid (BCAA) and decreased citrate were identified in the serum of preoperative NSCLC patients.Upregulation of BCKDK affected the metabolism of BCAAs and citrate in NSCLC cells. Knockout of BCKDK decreased the proliferation and exacerbated apoptosis of NSCLC cells ex vivo, while increased oxidative phosphorylation and, ROS levels, and inhibited glycolysis.Conclusions: BCKDK may influence glycolysis and oxidative phosphorylation by regulating the degradation of BCAA and citrate, thereby affecting the progression of NSCLC.

Immunometabolism – The Role of Branched-Chain Amino Acids

“…Consistent with the findings in terms of insulin resistance, the BCAA metabolism was also altered in various cancers ( vide supra ) ( 131 – 134 ). In a seminal article, Sivanand and Heiden reviewed the fundamental perspectives concerning the critical role of BCAA metabolism in cancer ( 143 ).…”

“…Several recent works highlighted the importance of the BCAA metabolism and BCKDK in cancers (131)(132)(133)(134)(135)(136)(137). It was shown that higher BCKDK expression was associated with shorter survival in colorectal cancer, and BCKDK could promote tumorigenesis in vivo and ex vivo through the mitogen-activated protein kinase (MAPK) signaling pathway (131).…”

“…Additionally, another study revealed the relation between non-small cell lung cancer (NSCLC) and BCKDK. It was observed that patients with NSCLC have higher BCAAs levels preoperatively in their blood compared to post-operative state and healthy individuals ( 134 ). Moreover, BCKDK level in NSCLC was also associated with poor prognosis and in vitro knockout of BCKDK decreased the proliferation of A549 and H1299 cell lines ( 134 ).…”

The Role of Branched-Chain Amino Acids and Branched-Chain α-Keto Acid Dehydrogenase Kinase in Metabolic Disorders

“…The phosphorylation rate of BCKDH represents BCKDK function as well. At the same time, the function of BCKDK in glucose metabolism can be measured by the uptake amount of glucose, the production level of lactate, the oxygen consumption rate in the cell, the extracellular acidification rate, and reactive oxygen species ( 23 , 24 ).…”

Inhibition of branched-chain alpha-keto acid dehydrogenase kinase augments the sensitivity of ovarian and breast cancer cells to paclitaxel

“…BCKDK expression is increased in high-grade ovarian cancer [ 27 ] and in chemotherapy-resistant disease [ 28 ]. In colorectal and non-small cell lung cancer, expression of BCKDK correlates with poor patient survival [ 12 , 29 ]. Apart from BCAA metabolism, BCKDK also regulates other cancer-relevant pathways through the direct phosphorylation of MEK [ 29 ] and ATP citrate lyase [ 30 ].…”