Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway

Abstract

Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts1. Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes2. Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA 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 Gln 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 Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via 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 tumors.

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…Several metabolic abnormalities are quite general, including a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis termed the Warburg effect, which is accompanied by lactate production and increased glucose uptake (Hsu & Sabatini, 2008). Other metabolic alterations are more tumor specific; different tumors differ in their dependence on glutamine (Son et al , 2013), serine (Possemato et al , 2011), or TCA cycle function (Selak et al , 2005; Dang et al , 2010). Yet, only few metabolic genes are presently known to be directly implicated in tumorigenesis.…”

Glutamine at focus: versatile roles in cancer

“…When the cytoplasmic environment is rich in glutamate, cysteine, glycine, and ATP, the enzyme glutathione synthetase generates reduced glutathione (GSH). A study using a panel of human cancer cell lines has shown that the intracellular redox balance between reduced and oxidized glutathione (GSSG) represents one of the most important antioxidant systems in cells [13]. Glutamate serves as a source of amino groups for NEAA production, particularly aspartate and alanine.…”

“…Medina and colleagues were the first to discuss the role of glutamine metabolism in cancer [45], but only recently, DeBerardinis et al have observed that transformed cells rely on glutamine metabolism to support the synthesis of protein and nucleotides, despite aerobic glycolysis. By using a 13 CNMR spectroscopy technique to study gliomas, the authors showed the catabolic fate Tumor Biol. of glutamine, which supports the synthesis of macromolecules and the intracellular redox balance.…”

“…In the cytoplasm, aspartate can be converted into OAA by the activity of aspartate transaminase (GOT1). Subsequently, OAA is converted to malate and pyruvate, which are used by malic enzyme (ME1) to sustain the NADPH/ NADP + ratio, which maintains cellular redox homeostasis [13]. Since the oncogenic K-ras-mutation is present in more than 95 % of PDAC, this oncogene has been considered as a master regulator pathway that uses glutamine metabolism to decrease intracellular ROS levels, contributing significantly to cell proliferation and tumorigenesis [59].…”

“…The metabolic state is primarily based on nutrients available to the tumors which have rewired their metabolic pathways, thereby contributing to this metabolic autonomy [5][6][7][8]. The discoveries of oncogenes and tumor suppressors that regulate nutrient uptake and its utilization have provided insights that nutrients per se play a pivotal role in cell growth and proliferation through a wide array of cell signaling pathways [9][10][11][12][13][14][15].…”