Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism

被引：136

作者：

Bott, Alex J. ^{[1
,2
]}

Shen, Jianliang ^{[1
]}

Tonelli, Claudia ^{[3
]}

Zhan, Le ^{[4
]}

Sivaram, Nithya ^{[5
,6
]}

Jiang, Ya-Ping ^{[5
,6
]}

Yu, Xufen ^{[7
,8
]}

Bhatt, Vrushank ^{[4
]}

Chiles, Eric ^{[4
,9
]}

Zhong, Hua ^{[1
]}

Maimouni, Sara ^{[1
]}

Dai, Weiwei ^{[1
]}

Velasquez, Stephani ^{[1
]}

Pan, Ji-An ^{[1
]}

Muthalagu, Nathiya ^{[10
]}

Morton, Jennifer ^{[10
]}

Anthony, Tracy G. ^{[11
]}

Feng, Hui ^{[12
,13
]}

Lamers, Wouter H. ^{[14
]}

Murphy, Daniel J. ^{[10
,15
]}

Guo, Jessie Yanxiang ^{[1
,4
,9
]}

Jin, Jian ^{[7
,8
]}

Crawford, Howard C. ^{[16
]}

Zhang, Lanjing ^{[1
,4
,17
]}

White, Eileen ^{[4
]}

Lin, Richard Z. ^{[5
,6
]}

Su, Xiaoyang ^{[4
,9
]}

Tuveson, David A. ^{[3
]}

Zong, Wei-Xing ^{[1
,4
]}

机构：

[1] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Chem Biol, Piscataway, NJ 08854 USA

[2] SUNY Stony Brook, Genet Grad Program, Stony Brook, NY USA

[3] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[4] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08901 USA

[5] SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA

[6] Northport VA Med Ctr, Northport, NY 11768 USA

[7] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Mt Sinai Ctr Therapeut Discovery, Dept Pharmacol Sci, New York, NY 10029 USA

[8] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Mt Sinai Ctr Therapeut Discovery, Dept Oncol Sci, New York, NY 10029 USA

[9] Rutgers Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08901 USA

[10] CRUK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[11] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08901 USA

[12] Boston Univ, Sch Med, Sect Hematol & Med Oncol, Dept Pharmacol,Canc Res Ctr, Boston, MA 02118 USA

[13] Boston Univ, Sch Med, Sect Hematol & Med Oncol, Dept Med,Canc Res Ctr, Boston, MA 02118 USA

[14] Univ Amsterdam, Acad Med Ctr, Tytgat Inst Liver & Intestinal Res, Amsterdam, Netherlands

[15] Univ Glasgow, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland

[16] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[17] Rutgers State Univ, Dept Biol Sci, Newark, NJ 07102 USA

来源：

CELL REPORTS | 2019年 / 29卷 / 05期

关键词：

NUCLEOTIDE BIOSYNTHESIS; TUMOR METABOLISM; SUPPORTS GROWTH; CELL BIOLOGY; SYNTHETASE; EXPRESSION; ADENOCARCINOMA; PROGRESSION; AMMONIA; MUSCLE;

D O I：

10.1016/j.celrep.2019.09.056

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to alpha-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras(G12D)-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.

引用

页码：1287 / +

页数：18

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