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

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

doi:10.1016/j.cmet.2014.03.003

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

Cell Metab. 2014 May 6;19(5):795-809. doi: 10.1016/j.cmet.2014.03.003. Epub 2014 Apr 10.

Authors

Han Xie¹, Jun-Ichi Hanai¹, Jian-Guo Ren¹, Lev Kats², Kerri Burgess³, Parul Bhargava⁴, Sabina Signoretti⁵, Julia Billiard⁶, Kevin J Duffy⁶, Aaron Grant⁷, Xiaoen Wang⁷, Pawel K Lorkiewicz⁸, Sabrina Schatzman⁸, Michael Bousamra 2nd⁹, Andrew N Lane⁸, Richard M Higashi⁸, Teresa W M Fan¹⁰, Pier Paolo Pandolfi¹¹, Vikas P Sukhatme¹², Pankaj Seth¹³

Affiliations

¹ 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.
² 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.
³ Division of Hematology-Oncology, 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.
⁴ Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
⁵ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
⁶ Cancer Metabolism DPU, GlaxoSmithKline, Collegeville, PA 19426, USA.
⁷ Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
⁸ Center for Regulatory and Environmental Analytical Metabolomics.
⁹ Department of Surgery, University of Louisville, Louisville, KY 40208, USA.
¹⁰ Center for Regulatory and Environmental Analytical Metabolomics. Electronic address: teresa.fan@uky.edu.
¹¹ Division of Genetics, 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.
¹² Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Division of Hematology-Oncology, 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.
¹³ 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. Electronic address: pseth@bidmc.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding