Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Division of Genetics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Cell Metab. 2014 May 6;19(5):795-809. doi: 10.1016/j.cmet.2014.03.003. Epub 2014 Apr 10.
The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the interconversion of pyruvate and lactate, is upregulated in human cancers, and is associated with aggressive tumor outcomes. Here we use an inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by reactivation of mitochondrial function in vitro, but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer-initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC, including cancer stem cell-dependent drug-resistant tumors.
乳酸脱氢酶-A（LDH-A）酶催化丙酮酸和乳酸的相互转化，在人类癌症中上调，并与侵袭性肿瘤结局相关。在这里，我们使用可诱导的小鼠模型，并证明在致癌性 K-RAS 或 EGFR 驱动的 NSCLC 小鼠模型中，LDH-A 的失活导致已建立的肿瘤中的肿瘤发生和疾病消退减少。我们还表明，LDH-A 的缺失导致丙酮酸代谢的重编程，在体外、体内和离体条件下乳酸发酵减少。这伴随着体外线粒体功能的重新激活，但在体内或离体条件下没有。最后，使用特定的小分子 LDH-A 抑制剂，我们证明 LDH-A 对于癌症起始细胞的存活和增殖是必不可少的。因此，LDH-A 可以成为 NSCLC 的一个可行的治疗靶点，包括依赖于癌症干细胞的耐药肿瘤。
