Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis

被引：228

作者：

Padanad, Mahesh S. ^{[1
,2
]}

Konstantinidou, Georgia ^{[1
,2
,12
]}

Venkateswaran, Niranjan ^{[1
,2
]}

Melegari, Margherita ^{[2
]}

Rindhe, Smita ^{[1
,2
]}

Mitsche, Matthew ^{[3
,4
]}

Yang, Chendong ^{[5
]}

Batten, Kimberly ^{[6
]}

Huffman, Kenneth E. ^{[7
]}

Liu, Jingwen ^{[8
]}

Tang, Ximing ^{[9
]}

Rodriguez-Canales, Jaime ^{[9
]}

Kalhor, Neda ^{[9
]}

Shay, Jerry W. ^{[6
]}

Minna, John D. ^{[1
,7
]}

McDonald, Jeffrey ^{[4
]}

Wistuba, Ignacio I. ^{[9
,10
,11
]}

DeBerardinis, Ralph J. ^{[3
,5
]}

Scaglioni, Pier Paolo ^{[1
,2
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA

[4] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr, Res Inst, Dallas, TX 75390 USA

[6] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA

[7] Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[8] Palo Alto Hlth Care Syst, Dept Vet Affairs, Palo Alto, CA 94304 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[12] Inselspital Bern, Inst Pharmacol, INO F, CH-3010 Bern, Switzerland

来源：

CELL REPORTS | 2016年 / 16卷 / 06期

关键词：

TUMOR INITIATION; MOUSE MODELS; RAS; CELLS; CANCER; PROGRESSION; EXPRESSION; GROWTH; GENE; MAINTENANCE;

D O I：

10.1016/j.celrep.2016.07.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and beta-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and beta-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain.

引用

页码：1614 / 1628

页数：15

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