title: 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.affiliation: 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.
authors.forename: Han
authors.initials: H
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hanai
authors.affiliation: 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.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Lev
authors.initials: L
authors.lastname: Kats
authors.affiliation: 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.
authors.forename: Kerri
authors.initials: K
authors.lastname: Burgess
authors.affiliation: Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Bhargava
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Cancer Metabolism DPU, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Billiard
authors.affiliation: Cancer Metabolism DPU, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Duffy
authors.affiliation: 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.
authors.forename: Aaron
authors.initials: A
authors.lastname: Grant
authors.affiliation: 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.
authors.forename: Xiaoen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Lorkiewicz
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schatzman
authors.affiliation: Department of Surgery, University of Louisville, Louisville, KY 40208, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bousamra
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Lane
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Higashi
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics. Electronic address: teresa.fan@uky.edu.
authors.forename: Teresa W M
authors.initials: TW
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: 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.
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
authors.affiliation: 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.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D066246:ErbB Receptors; D015689:Oncogene Protein p21(ras)
references.citation: Cancer Cell. 2005 Oct;8(4):311-21
references.pmid: 16226706
references.citation: Cell. 2008 Sep 5;134(5):703-7
references.pmid: 18775299
references.citation: J Med Chem. 2012 Apr 12;55(7):3285-306
references.pmid: 22417091
references.citation: Semin Radiat Oncol. 2009 Apr;19(2):106-11
references.pmid: 19249648
references.citation: Magn Reson Med. 2007 Jul;58(1):65-9
references.pmid: 17659629
references.citation: EMBO J. 2012 May 2;31(9):2103-16
references.pmid: 22446391
references.citation: Nat Cell Biol. 2012 Aug;14(8):859-64
references.pmid: 22750943
references.citation: Biochem J. 1996 Feb 1;313 ( Pt 3):809-14
references.pmid: 8611159
references.citation: Cancer Res. 2005 Jan 1;65(1):226-35
references.pmid: 15665299
references.citation: Metabolomics. 2011 Jun 1;7(2):257-269
references.pmid: 21666826
references.citation: Blood. 2007 May 1;109(9):3812-9
references.pmid: 17255361
references.citation: Cancer Res. 2005 Jul 1;65(13):5512-5
references.pmid: 15994921
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: J Med Chem. 2013 Feb 14;56(3):1023-40
references.pmid: 23302067
references.citation: Cancer Cell. 2007 Jan;11(1):37-51
references.pmid: 17222789
references.citation: Cancer Lett. 2012 Aug 1;321(1):45-54
references.pmid: 22429998
references.citation: Br J Cancer. 2006 Jan 30;94(2):318-22
references.pmid: 16421597
references.citation: Nat Rev Cancer. 2004 Nov;4(11):891-9
references.pmid: 15516961
references.citation: Cell Metab. 2012 Jun 6;15(6):827-37
references.pmid: 22682223
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Neoplasia. 2011 Jan;13(1):60-71
references.pmid: 21245941
references.citation: Proc Am Thorac Soc. 2009 Apr 15;6(2):201-5
references.pmid: 19349489
references.citation: Cell Death Dis. 2013 Jun 27;4:e696
references.pmid: 23807225
references.citation: Methods Cell Biol. 2008;84:541-88
references.pmid: 17964943
references.citation: Clin Exp Metastasis. 2005;22(1):25-30
references.pmid: 16132575
references.citation: Cancer Metab. 2013 Sep 06;1(1):19
references.pmid: 24280423
references.citation: PLoS One. 2007 Aug 29;2(8):e810
references.pmid: 17726540
references.citation: Cancer Cell. 2013 Aug 12;24(2):213-228
references.pmid: 23911236
references.citation: Nat Rev Cancer. 2007 Sep;7(9):645-58
references.pmid: 17687385
references.citation: PLoS Genet. 2012;8(3):e1002573
references.pmid: 22438825
references.citation: Lung Cancer. 2007 Oct;58(1):95-103
references.pmid: 17610986
references.citation: Curr Opin Biotechnol. 2007 Oct;18(5):460-6
references.pmid: 18023337
references.citation: Mol Cell Biol. 2011 Dec;31(24):4938-50
references.pmid: 21969607
references.citation: Mol Cancer Ther. 2009 Mar;8(3):626-35
references.pmid: 19276158
references.citation: N Engl J Med. 2005 Feb 24;352(8):786-92
references.pmid: 15728811
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2037-42
references.pmid: 20133848
references.citation: Breast Cancer Res Treat. 2012 Feb;131(3):791-800
references.pmid: 21452021
references.citation: Novartis Found Symp. 2001;240:1-6
references.pmid: 11727923
references.citation: Oncogene. 2013 Oct 31;32(44):5210-9
references.pmid: 23208505
references.citation: Pharmacol Ther. 2012 Mar;133(3):366-91
references.pmid: 22212615
references.citation: Genes Dev. 2001 Dec 15;15(24):3249-62
references.pmid: 11751631
references.citation: Bioorg Med Chem Lett. 2013 Jun 1;23(11):3186-94
references.pmid: 23628333
references.citation: J Natl Cancer Inst. 1999 Feb 17;91(4):299-301
references.pmid: 10050857
references.citation: Am J Pathol. 1997 Feb;150(2):409-15
references.pmid: 9033256
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683
references.citation: Cancer Cell. 2006 Jun;9(6):425-34
references.pmid: 16766262