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; 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

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, Andrew N. Lane, Richard M. Higashi, Teresa W.M. Fan, Pier Paolo Pandolfi, Vikas P. Sukhatme, Pankaj Seth

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366 Scopus citations

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.

Original language	English
Pages (from-to)	795-809
Number of pages	15
Journal	Cell Metabolism
Volume	19
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2014.03.003
State	Published - May 6 2014

Bibliographical note

Funding Information:
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 and 1R01GM098453 (to P.S.), 1P01CA163223-01A1 (to A.N.L. and T.W.M.F.), 1U24DK097215-01A1 (to R.M.H., T.W.M.F., and A.N.L.), administrative supplement RM-11-024 (to P.S. and T.W.M.F.), R21EB01447 (to A.G.), and startup funds from the Department of Medicine, BIDMC (to P.S.). We would like to thank H. Varmus for providing the K-RAS animals, K. Wong for the EGFR-T790M mice, and J. Tan and R. Balasubramaniam for processing the mouse and human tissue slice samples for SIRM analysis. J.B. and K.J.D. are emplyoees of GlaxoSmithKline.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2014.03.003

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Xie, H., Hanai, J. I., Ren, J. G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K. J., Grant, A., Wang, X., Lorkiewicz, P. K., Schatzman, S., Bousamra, M., Lane, A. N., Higashi, R. M., Fan, T. W. M., Pandolfi, P. P., Sukhatme, V. P., & Seth, P. (2014). Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metabolism, 19(5), 795-809. https://doi.org/10.1016/j.cmet.2014.03.003

@article{7db22c88abcd45f5a856258230f49f7f,

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.",

author = "Han Xie and Hanai, {Jun Ichi} and Ren, {Jian Guo} and Lev Kats and Kerri Burgess and Parul Bhargava and Sabina Signoretti and Julia Billiard and Duffy, {Kevin J.} and Aaron Grant and Xiaoen Wang and Lorkiewicz, {Pawel K.} and Sabrina Schatzman and Michael Bousamra and Lane, {Andrew N.} and Higashi, {Richard M.} and Fan, {Teresa W.M.} and Pandolfi, {Pier Paolo} and Sukhatme, {Vikas P.} and Pankaj Seth",

note = "Funding Information: 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 and 1R01GM098453 (to P.S.), 1P01CA163223-01A1 (to A.N.L. and T.W.M.F.), 1U24DK097215-01A1 (to R.M.H., T.W.M.F., and A.N.L.), administrative supplement RM-11-024 (to P.S. and T.W.M.F.), R21EB01447 (to A.G.), and startup funds from the Department of Medicine, BIDMC (to P.S.). We would like to thank H. Varmus for providing the K-RAS animals, K. Wong for the EGFR-T790M mice, and J. Tan and R. Balasubramaniam for processing the mouse and human tissue slice samples for SIRM analysis. J.B. and K.J.D. are emplyoees of GlaxoSmithKline. ",

year = "2014",

month = may,

day = "6",

doi = "10.1016/j.cmet.2014.03.003",

language = "English",

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pages = "795--809",

number = "5",

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Xie, H, Hanai, JI, Ren, JG, Kats, L, Burgess, K, Bhargava, P, Signoretti, S, Billiard, J, Duffy, KJ, Grant, A, Wang, X, Lorkiewicz, PK, Schatzman, S, Bousamra, M, Lane, AN , Higashi, RM , Fan, TWM, Pandolfi, PP, Sukhatme, VP & Seth, P 2014, 'Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells', Cell Metabolism, vol. 19, no. 5, pp. 795-809. https://doi.org/10.1016/j.cmet.2014.03.003

TY - JOUR

T1 - Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells

AU - Xie, Han

AU - Hanai, Jun Ichi

AU - Ren, Jian Guo

AU - Kats, Lev

AU - Burgess, Kerri

AU - Bhargava, Parul

AU - Signoretti, Sabina

AU - Billiard, Julia

AU - Duffy, Kevin J.

AU - Grant, Aaron

AU - Wang, Xiaoen

AU - Lorkiewicz, Pawel K.

AU - Schatzman, Sabrina

AU - Bousamra, Michael

AU - Lane, Andrew N.

AU - Higashi, Richard M.

AU - Fan, Teresa W.M.

AU - Pandolfi, Pier Paolo

AU - Sukhatme, Vikas P.

AU - Seth, Pankaj

N1 - Funding Information: 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 and 1R01GM098453 (to P.S.), 1P01CA163223-01A1 (to A.N.L. and T.W.M.F.), 1U24DK097215-01A1 (to R.M.H., T.W.M.F., and A.N.L.), administrative supplement RM-11-024 (to P.S. and T.W.M.F.), R21EB01447 (to A.G.), and startup funds from the Department of Medicine, BIDMC (to P.S.). We would like to thank H. Varmus for providing the K-RAS animals, K. Wong for the EGFR-T790M mice, and J. Tan and R. Balasubramaniam for processing the mouse and human tissue slice samples for SIRM analysis. J.B. and K.J.D. are emplyoees of GlaxoSmithKline.

PY - 2014/5/6

Y1 - 2014/5/6

N2 - 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.

AB - 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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DO - 10.1016/j.cmet.2014.03.003

M3 - Article

C2 - 24726384

AN - SCOPUS:84900296103

SN - 1550-4131

VL - 19

SP - 795

EP - 809

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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