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.
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This work was supported in part by Department of Defense award PC094151 (to P.S), grants for target award 2012-01-0602 (to P.S), NIH grants 5R01CA152330, 1R01GM098453 (to P.S), 1P01CA163223-01A1 (to A.N.L and T.F), 1U24DK097215-01A1 (to R.M.H, T.F, and A.N.L) and administrative supplement RM-11-024 (to P.S & T.F), R21EB01447 (to A.G) and startup funds from the Department of Medicine, BIDMC (to P.S).
Xie, Han; Hanai, Jun-Ichi; Ren, Jian-Guo; Kats, Lev; Burgess, Kerri; Bhargava, Parul; Signoretti, Sabina; Billiard, Julia; Duffy, Kevin J.; Grant, Aaron; Wang, Xiaoen; Lorkiewicz, Pawel; Schatzman, Sabrina; Bousamra, Michael; Lane, Andrew N.; Higashi, Richard M.; Fan, Teresa W-M; Pandolfi, Pier Paolo; Sukhatme, Vikas P.; and Seth, Pankaj, "Targeting Lactate Dehydrogenase-A Inhibits Tumorigenesis and Tumor Progression in Mouse Models of Lung Cancer and Impacts Tumor-Initiating Cells" (2014). Toxicology and Cancer Biology Faculty Publications. 48.