Deng 2022 Cell Mol Life Sci

From Bioblast
Jump to navigation Jump to search
Publications in the MiPMap
Deng H, Gao Y, Trappetti V, Hertig D, Karatkevich D, Losmanova T, Urzi C, Ge H, Geest GA, Bruggmann R, Djonov V, Nuoffer JM, Vermathen P, Zamboni N, Riether C, Ochsenbein A, Peng RW, Kocher GJ, Schmid RA, Dorn P, Marti TM (2022) Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage. https://doi.org/10.1007/s00018-022-04453-5

» Cell Mol Life Sci 79:445. PMID: 35877003 Open Access

Deng Haibin, Gao Yanyun, Trappetti Verdiana, Hertig Damian, Karatkevich Darya, Losmanova Tereza, Urzi Christian, Ge Huixiang, Geest Gerrit Adriaan, Bruggmann Remy, Djonov Valentin, Nuoffer Jean-Marc, Vermathen Peter, Zamboni Nicola, Riether Carsten, Ochsenbein Adrian, Peng Ren-Wang, Kocher Gregor Jan, Schmid Ralph Alexander, Dorn Patrick, Marti Thomas Michael (2022) Cell Mol Life Sci

Abstract: Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate metabolism. We show that silencing of LDHB induces persistent mitochondrial DNA damage, decreases mitochondrial respiratory complex activity and OXPHOS, resulting in reduced levels of mitochondria-dependent metabolites, e.g., TCA intermediates, amino acids, and nucleotides. Inhibition of LDHB dramatically reduced the survival of tumor-initiating cells and sphere formation in vitro, which can be partially restored by nucleotide supplementation. In addition, LDHB silencing reduced tumor initiation and growth of xenograft tumors. Furthermore, we report for the first time that homozygous deletion of LDHB significantly reduced lung tumorigenesis upon the concomitant loss of Tp53 and expression of oncogenic KRAS without considerably affecting the animal's health status, thereby identifying LDHB as a potential target for NSCLC therapy. In conclusion, our study shows for the first time that LDHB is essential for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, demonstrating that LDHB is crucial for the survival and proliferation of NSCLC tumor-initiating cells and tumorigenesis. Keywords: Cancer stem cells, Cellular plasticity, Lung cancer, Mitochondrial DNA, Mitochondrial metabolism, Nucleotide metabolism, Tumorigenicity Bioblast editor: Plangger M O2k-Network Lab: CH Bern Nuoffer JM


Labels: MiParea: Respiration, mtDNA;mt-genetics, nDNA;cell genetics  Pathology: Cancer 

Organism: Human  Tissue;cell: Endothelial;epithelial;mesothelial cell  Preparation: Permeabilized cells 


Coupling state: LEAK  Pathway: N, S, CIV, ROX  HRR: Oxygraph-2k