MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4

Candice Sun Hong; Nicholas A Graham; Wen Gu; Carolina Espindola Camacho; Vei Mah; Erin L Maresh; Mohammed Alavi; Lora Bagryanova; Pascal A L Krotee; Brian K Gardner; Iman Saramipoor Behbahan; Steve Horvath; David Chia; Ingo K Mellinghoff; Sara A Hurvitz; Steven M Dubinett; Susan E Critchlow; Siavash K Kurdistani; Lee Goodglick; Daniel Braas; Thomas G Graeber; Heather R Christofk

doi:10.1016/j.celrep.2016.01.057

MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4

Cell Rep. 2016 Feb 23;14(7):1590-1601. doi: 10.1016/j.celrep.2016.01.057. Epub 2016 Feb 11.

Authors

Candice Sun Hong¹, Nicholas A Graham², Wen Gu¹, Carolina Espindola Camacho¹, Vei Mah³, Erin L Maresh³, Mohammed Alavi³, Lora Bagryanova³, Pascal A L Krotee¹, Brian K Gardner⁴, Iman Saramipoor Behbahan⁵, Steve Horvath⁶, David Chia⁷, Ingo K Mellinghoff⁸, Sara A Hurvitz⁹, Steven M Dubinett¹⁰, Susan E Critchlow¹¹, Siavash K Kurdistani¹², Lee Goodglick⁷, Daniel Braas¹³, Thomas G Graeber¹⁴, Heather R Christofk¹⁵

Affiliations

¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Biostatistics, Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Neurology, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 USA; Department of Pharmacology, Weill-Cornell Medical College, New York, NY 10065, USA.
⁹ Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
¹² Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

Abstract

Monocarboxylate transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here, we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients. Acute MCT1 inhibition reduces pyruvate export but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that co-express MCT1 and MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest MCT1 expression is elevated in glycolytic cancers to promote pyruvate export that when inhibited, enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors, further supporting their use as anti-cancer therapeutics.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Biological Transport
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Citric Acid Cycle / drug effects
Citric Acid Cycle / genetics
Epithelial Cells / drug effects
Epithelial Cells / metabolism
Epithelial Cells / pathology
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Glycolysis / drug effects
Glycolysis / genetics
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Monocarboxylic Acid Transporters / antagonists & inhibitors
Monocarboxylic Acid Transporters / genetics*
Monocarboxylic Acid Transporters / metabolism
Muscle Proteins / genetics*
Muscle Proteins / metabolism
Oxidative Phosphorylation / drug effects
Pyrimidinones / pharmacology
Pyruvic Acid / metabolism*
Signal Transduction
Symporters / antagonists & inhibitors
Symporters / genetics*
Symporters / metabolism
Thiophenes / pharmacology
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

AZD3965
Antineoplastic Agents
Monocarboxylic Acid Transporters
Muscle Proteins
Pyrimidinones
Slc16a4 protein, mouse
Symporters
Thiophenes
monocarboxylate transport protein 1
Pyruvic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding