Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells.

Abstract

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.

• Authors: Han Xie, Jun-Ichi Hanai, Jian-Guo Ren, Lev Kats, Kerri Burgess, Parul Bhargava, Sabina Signoretti, Julia Billiard, Kevin J Duffy, Aaron Grant, Xiaoen Wang, Pawel K Lorkiewicz, Sabrina Schatzman, Michael Bousamra 2nd, Andrew N Lane, Richard M Higashi, Teresa W M Fan, Pier Paolo Pandolfi, Vikas P Sukhatme, Pankaj Seth
• Journal: Cell metabolism (Cell Metab) Vol. 19 Issue 5 Pg. 795-809 (May 06 2014) ISSN: 1932-7420 [Electronic] United States
• PMID: 24726384 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Isoenzymes
• Pyruvic Acid
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• ErbB Receptors
• Oncogene Protein p21(ras)

Topics

• Animals
• Carcinogenesis (metabolism)
• Carcinoma, Non-Small-Cell Lung (metabolism)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Cell Survival (physiology)
• Cell Transformation, Neoplastic (metabolism)
• Disease Progression
• ErbB Receptors (metabolism)
• Hep G2 Cells
• Humans
• Isoenzymes (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Lactate Dehydrogenase 5
• Lung Neoplasms (metabolism)
• Mice
• Mitochondria (metabolism)
• Oncogene Protein p21(ras) (metabolism)
• Pyruvic Acid (metabolism)