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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743533 | PMC |
| http://dx.doi.org/10.21037/tlcr-21-885 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.
Mov Disord
January 2025
Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Background: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.
Methods: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs.
BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.
Acta Neuropathol Commun
December 2024
Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function.
View Article and Find Full Text PDFBicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity.
ACS Med Chem Lett
November 2024
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9038, United States.
Elevated levels of the branched chain α-amino acids valine, leucine, and isoleucine are associated with heart disease and metabolic disorders. The kinase BDK, also known as branched-chain ketoacid dehydrogenase kinase (BCKDK), is a negative regulator of branched-chain α-amino acid metabolism through deactivation of BCKDC, the branched-chain α-ketoacid dehydrogenase complex. Inhibitors of BDK increase the activity of BCKDC and could be useful therapeutic leads for cardiometabolic diseases.
View Article and Find Full Text PDFBCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA.
Cell Death Dis
October 2024
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Article Synopsis
- * Mice lacking the BCKDK enzyme in the liver showed normal blood sugar levels but had reduced glucose production and key gluconeogenic enzyme expression, while those lacking BCKDHA did not show these abnormalities.
- * BT2 treatment inhibited BCKDK and reduced glucose production in liver cells, suggesting that BCKDK influences glucose production through specific proteins (CREB and FOXO1) without relying on BCKDHA's role in BCAA breakdown.
The genetic cause of neurodevelopmental disorders in 30 consanguineous families.
Front Med (Lausanne)
August 2024
Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile Des Aveugles, Lausanne, Switzerland.
Objective: This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs).
Methods: We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!