Once considered a waste product of anaerobic cellular metabolism, lactate has emerged as a critical regulator of cancer development, maintenance, and metastasis. The putative major function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in cancer cell metabolism remains poorly understood. This project aims to investigate how LDHB regulates cancer cell metabolism, especially mitochondria-dependent metabolism.. LDHB-dependent mitochondrial metabolism is essential for tumorigenesis but not for proliferation of NSCLC cells

Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of cancer development, maintenance, and metastasis. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in cancer cell metabolism is not yet well elucidated. Here we show that acute LDHB silencing abrogated proliferation, sphere, and colony formation in all lung cancer cell lines tested regardless of the KRAS mutation status. Silencing LDHB eliminated subpopulations associated with increased tumor initiation capacity and reduced not only mitochondria-dependent oxidative phosphorylation but also glycolysis. Expression of mitochondrial genes and signaling pathways associated with DNA replication stress was reduced by LDHB silencing, as were levels of mitochondria-dependent metabolites, e.g., TCA intermediates, energy carriers, amino acids, and nucleotides. Consequently, nuclear and mitochondrial DNA damage levels increased after silencing of LDHB, accompanied by activation of the innate immune response. Surprisingly, lung cancer cells partially adapted to the long-term silencing of LDHB, i.e., nuclear DNA damage levels normalized, and the proliferative capacity was restored. In contrast, sphere and tumor initiation ability continued to be suppressed, mitochondrial DNA integrity could not be restored, suggesting that LDHB is important for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, and thus for tumorigenesis, but not for long-term proliferation of NSCLC cells.