Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress

被引：390

作者：

Zaugg, Kathrin ^{[1
,2
,3
,4
,5
,6
]}

Yao, Yi ^{[7
]}

Reilly, Patrick T. ^{[1
,8
]}

Kannan, Karuppiah ^{[9
]}

Kiarash, Reza ^{[7
]}

Mason, Jacqueline ^{[7
]}

Huang, Ping ^{[7
]}

Sawyer, Suzanne K. ^{[10
]}

Fuerth, Benjamin ^{[11
]}

Faubert, Brandon ^{[11
]}

Kalliomaeki, Tuula ^{[12
]}

Elia, Andrew ^{[1
,2
,3
,4
,5
]}

Luo, Xunyi ^{[7
]}

Nadeem, Vincent ^{[7
]}

Bungard, David ^{[13
]}

Yalavarthi, Sireesha ^{[9
]}

Growney, Joseph D. ^{[9
]}

Wakeham, Andrew ^{[1
,2
,3
,4
,5
]}

Moolani, Yasmin ^{[1
,2
,3
,4
,5
]}

Silvester, Jennifer ^{[1
,2
,3
,4
,5
]}

Ten, Annick You ^{[1
,2
,3
,4
,5
]}

Bakker, Walbert ^{[1
]}

Tsuchihara, Katsuya ^{[1
]}

Berger, Shelley L. ^{[13
]}

Hill, Richard P. ^{[2
,3
,4
,5
,12
]}

Jones, Russell G. ^{[11
]}

Tsao, Ming ^{[10
]}

Robinson, Murray O. ^{[9
]}

Thompson, Craig B. ^{[14
,15
,16
]}

Pan, Guohua ^{[7
]}

Mak, Tak W. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Univ Toronto, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2C1, Canada

[2] Univ Toronto, Dept Immunol, Toronto, ON M5G 2C1, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1, Canada

[4] Ontario Canc Inst, Toronto, ON M5G 2C1, Canada

[5] Univ Hlth Network, Toronto, ON M5G 2C1, Canada

[6] Univ Hosp, Lab Appl Radiat Oncol, Dept Radiat Oncol, CH-8091 Zurich, Switzerland

[7] Campbell Family Inst Breast Canc Res MaRS, Toronto, ON M5G 1L7, Canada

[8] Natl Canc Ctr, Lab Inflammat Biol, Dept Cellular & Mol Res, Singapore 169610, Singapore

[9] AVEO Pharmaceut Inc, Cambridge, MA 02139 USA

[10] Princess Margaret Hosp, Dept Lab Med & Pathobiol, Toronto, ON M5G 2M9, Canada

[11] McGill Univ, Dept Physiol, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada

[12] Princess Margaret Hosp, Appl Mol Oncol Div, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada

[13] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

[14] Univ Penn, Dept Canc Biol, Philadelphia, PA 19104 USA

[15] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[16] Univ Penn, Fac Med, Philadelphia, PA 19104 USA

来源：

GENES & DEVELOPMENT | 2011年 / 25卷 / 10期

基金：

加拿大健康研究院;

关键词：

CPT1C; fatty acid homeostasis; metabolic stress; rapamycin resistance; xenograft tumors; BREAST-TUMORS; KINASE AMPK; MOUSE MODEL; CANCER; GENE; PHOSPHORYLATION; GLYCOLYSIS; CHECKPOINT; RECEPTOR; DISEASE;

D O I：

10.1101/gad.1987211

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPK alpha. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.

引用

页码：1041 / 1051

页数：11

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