Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.
Department for BioMedical Research, University of Bern, Bern, Switzerland.
Cell Mol Life Sci. 2022 Jul 25;79(8):445. doi: 10.1007/s00018-022-04453-5.
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.
曾经被认为是厌氧细胞代谢的废物产物，乳酸已被确定为肿瘤发生、维持和进展的关键调节剂。乳酸脱氢酶 B (LDHB) 的假定主要功能是催化乳酸转化为丙酮酸；然而，其在肿瘤发生过程中调节代谢的作用在很大程度上是未知的。为了确定 LDHB 是否在肿瘤发生中发挥关键作用，我们进行了二维和三维体外实验，利用传统的异种移植肿瘤模型，并开发了一种新型非小细胞肺癌（NSCLC）的基因工程小鼠模型（GEMM），在该模型中，我们将 LDHB 缺失等位基因与由 p53（也称为 Trp53）同时缺失和致癌 KRAS（G12D）（KP）表达驱动的肺腺癌诱导模型相结合。在这里，我们表明上皮样、起始性 NSCLC 细胞具有氧化磷酸化（OXPHOS）表型，受 LDHB 介导的乳酸代谢调节。我们表明，沉默 LDHB 会诱导持续的线粒体 DNA 损伤，降低线粒体呼吸复合物活性和 OXPHOS，导致依赖线粒体的代谢物水平降低，例如 TCA 中间产物、氨基酸和核苷酸。LDHB 抑制显著降低了肿瘤起始细胞的存活率和球体形成能力，这可以通过核苷酸补充部分恢复。此外，LDHB 沉默减少了异种移植肿瘤的起始和生长。此外，我们首次报道，在同时缺失 Tp53 和表达致癌 KRAS 的情况下，LDHB 纯合缺失显著降低了肺肿瘤发生，而不会显著影响动物的健康状况，从而确定 LDHB 是 NSCLC 治疗的潜在靶点。总之，我们的研究首次表明 LDHB 对于维持线粒体代谢，特别是核苷酸代谢是必不可少的，证明 LDHB 对于 NSCLC 肿瘤起始细胞的存活和增殖以及肿瘤发生至关重要。
