Cancer cells have metabolic dependencies that distinguish them from their normal counterparts1. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes2. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
We would like to thank D. Anastasiou for advice and helpful comments on the manuscript; M. Yuan and S. Breitkopf for technical help with mass spectrometry experiments; J. Erickson, R. Cerione and J. Escobedo for the GLS inhibitors. Grant support derives from the Dana Farber Cancer Institute (A.C.K.), National Cancer Institute Grant R01 CA157490 (A.C.K.), Kimmel Scholar Award (A.C.K.), AACR-PanCAN Career Development Award (A.C.K.), NIH grants T32 CA009382-26 (H.Y.) and P01 CA117969 (L.C.C. and R.A.D.). C.A.L. is the Amgen Fellow of the Damon Runyon Cancer Research Foundation (DRG-2056-10). NIH grants 5P01CA120964-05 and Dana–Farber/Harvard Cancer Center Support Grant 5P30CA006516-46 (J.M.A.).
This file contains Supplementary Figures 1-21 and Primer Sequences for qRT-PCR.
About this article
Ischemic Neuroprotectant PKCε Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury
Translational Stroke Research (2019)