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

Alex J. Bott; Jianliang Shen; Claudia Tonelli; Le Zhan; Nithya Sivaram; Ya Ping Jiang; Xufen Yu; Vrushank Bhatt; Eric Chiles; Hua Zhong; Sara Maimouni; Weiwei Dai; Stephani Velasquez; Ji An Pan; Nathiya Muthalagu; Jennifer Morton; Tracy G. Anthony; Hui Feng; Wouter H. Lamers; Daniel J. Murphy; Jessie Yanxiang Guo; Jian Jin; Howard C. Crawford; Lanjing Zhang; Eileen White; Richard Z. Lin; Xiaoyang Su; David A. Tuveson; Wei Xing Zong

doi:10.1016/j.celrep.2019.09.056

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

Alex J. Bott, Jianliang Shen, Claudia Tonelli, Le Zhan, Nithya Sivaram, Ya Ping Jiang, Xufen Yu, Vrushank Bhatt, Eric Chiles, Hua Zhong, Sara Maimouni, Weiwei Dai, Stephani Velasquez, Ji An Pan, Nathiya Muthalagu, Jennifer Morton, Tracy G. Anthony, Hui Feng, Wouter H. Lamers, Daniel J. MurphyJessie Yanxiang Guo, Jian Jin, Howard C. Crawford, Lanjing Zhang, Eileen White, Richard Z. Lin, Xiaoyang Su, David A. Tuveson, Wei Xing Zong

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108 Scopus citations

Abstract

Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-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.

Original language	English (US)
Pages (from-to)	1287-1298.e6
Journal	Cell Reports
Volume	29
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2019.09.056
State	Published - Oct 29 2019

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

Keywords

K-Ras
glutamate ammonia ligase
glutamine
glutamine synthetase
hexosamine
nitrogen metabolism
nucleotide
pancreatic cancer
α-ketoglutarate

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10.1016/j.celrep.2019.09.056

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Bott, A. J., Shen, J., Tonelli, C., Zhan, L., Sivaram, N., Jiang, Y. P., Yu, X., Bhatt, V., Chiles, E., Zhong, H., Maimouni, S., Dai, W., Velasquez, S., Pan, J. A., Muthalagu, N., Morton, J., Anthony, T. G., Feng, H., Lamers, W. H., ... Zong, W. X. (2019). Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism. Cell Reports, 29(5), 1287-1298.e6. https://doi.org/10.1016/j.celrep.2019.09.056

@article{594b253f0ab94604adc30b1a98145eaf,

title = "Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism",

abstract = "Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-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 KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.",

keywords = "K-Ras, glutamate ammonia ligase, glutamine, glutamine synthetase, hexosamine, nitrogen metabolism, nucleotide, pancreatic cancer, α-ketoglutarate",

author = "Bott, {Alex J.} and Jianliang Shen and Claudia Tonelli and Le Zhan and Nithya Sivaram and Jiang, {Ya Ping} and Xufen Yu and Vrushank Bhatt and Eric Chiles and Hua Zhong and Sara Maimouni and Weiwei Dai and Stephani Velasquez and Pan, {Ji An} and Nathiya Muthalagu and Jennifer Morton and Anthony, {Tracy G.} and Hui Feng and Lamers, {Wouter H.} and Murphy, {Daniel J.} and Guo, {Jessie Yanxiang} and Jian Jin and Crawford, {Howard C.} and Lanjing Zhang and Eileen White and Lin, {Richard Z.} and Xiaoyang Su and Tuveson, {David A.} and Zong, {Wei Xing}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = oct,

day = "29",

doi = "10.1016/j.celrep.2019.09.056",

language = "English (US)",

volume = "29",

pages = "1287--1298.e6",

journal = "Cell Reports",

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Bott, AJ, Shen, J, Tonelli, C, Zhan, L, Sivaram, N, Jiang, YP, Yu, X, Bhatt, V, Chiles, E, Zhong, H, Maimouni, S, Dai, W, Velasquez, S, Pan, JA, Muthalagu, N, Morton, J, Anthony, TG, Feng, H, Lamers, WH, Murphy, DJ, Guo, JY, Jin, J, Crawford, HC, Zhang, L , White, E, Lin, RZ, Su, X, Tuveson, DA & Zong, WX 2019, 'Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism', Cell Reports, vol. 29, no. 5, pp. 1287-1298.e6. https://doi.org/10.1016/j.celrep.2019.09.056

TY - JOUR

T1 - Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism

AU - Bott, Alex J.

AU - Shen, Jianliang

AU - Tonelli, Claudia

AU - Zhan, Le

AU - Sivaram, Nithya

AU - Jiang, Ya Ping

AU - Yu, Xufen

AU - Bhatt, Vrushank

AU - Chiles, Eric

AU - Zhong, Hua

AU - Maimouni, Sara

AU - Dai, Weiwei

AU - Velasquez, Stephani

AU - Pan, Ji An

AU - Muthalagu, Nathiya

AU - Morton, Jennifer

AU - Anthony, Tracy G.

AU - Feng, Hui

AU - Lamers, Wouter H.

AU - Murphy, Daniel J.

AU - Guo, Jessie Yanxiang

AU - Jin, Jian

AU - Crawford, Howard C.

AU - Zhang, Lanjing

AU - White, Eileen

AU - Lin, Richard Z.

AU - Su, Xiaoyang

AU - Tuveson, David A.

AU - Zong, Wei Xing

PY - 2019/10/29

Y1 - 2019/10/29

N2 - Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-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 KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.

AB - Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-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 KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.

KW - K-Ras

KW - glutamate ammonia ligase

KW - glutamine

KW - glutamine synthetase

KW - hexosamine

KW - nitrogen metabolism

KW - nucleotide

KW - pancreatic cancer

KW - α-ketoglutarate

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UR - http://www.scopus.com/inward/citedby.url?scp=85073991373&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.09.056

DO - 10.1016/j.celrep.2019.09.056

M3 - Article

C2 - 31665640

AN - SCOPUS:85073991373

SN - 2211-1247

VL - 29

SP - 1287-1298.e6

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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