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

被引：183

作者：

Hong, Candice Sun ^{[1
]}

Graham, Nicholas A. ^{[1
,2
]}

Gu, Wen ^{[1
]}

Camacho, Carolina Espindola ^{[1
]}

Mah, Vei ^{[4
]}

Maresh, Erin L. ^{[4
]}

Alavi, Mohammed ^{[4
]}

Bagryanova, Lora ^{[4
]}

Krotee, Pascal A. L. ^{[1
]}

Gardner, Brian K. ^{[5
]}

Behbahan, Iman Saramipoor ^{[6
]}

Horvath, Steve ^{[7
,11
]}

Chia, David ^{[4
,11
]}

Mellinghoff, Ingo K. ^{[8
,9
]}

Hurvitz, Sara A. ^{[10
,11
]}

Dubinett, Steven M. ^{[1
,4
,11
]}

Critchlow, Susan E. ^{[12
]}

Kurdistani, Siavash K. ^{[6
,11
,13
]}

Goodglick, Lee ^{[4
,11
]}

Braas, Daniel ^{[1
,3
]}

Graeber, Thomas G. ^{[1
,2
,3
,11
]}

Christofk, Heather R. ^{[1
,3
,11
,13
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Crump Inst Mol Imaging, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Metabol Ctr, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biostat, Dept Human Genet, Los Angeles, CA 90095 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Neurol, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[9] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA

[10] Univ Calif Los Angeles, Div Hematol Oncol, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[12] AstraZeneca, Oncol iMed, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[13] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

来源：

CELL REPORTS | 2016年 / 14卷 / 07期

关键词：

MONOCARBOXYLATE TRANSPORTER 1; LACTATE/H+ SYMPORTERS MCT1; BREAST-CANCER; LUNG-CANCER; EXPRESSION; SURVIVAL; WOMEN; CD147/EMMPRIN; PROGRESSION; INTEGRATION;

D O I：

10.1016/j.celrep.2016.01.057

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1590 / 1601

页数：12

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