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.
journal_name
Cell Repjournal_title
Cell reportsauthors
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,Zhangdoi
10.1016/j.celrep.2019.09.056subject
Has Abstractpub_date
2019-10-29 00:00:00pages
1287-1298.e6issue
5issn
2211-1247pii
S2211-1247(19)31244-6journal_volume
29pub_type
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