Pyruvate is then imported into the mitochondria, where it is converted into acetyl CoA for entry into the tricarboxylic acid (TCA) cycle.
Normal, non-proliferating cells primarily convert glucose to pyruvate via glycolysis. The shift toward anabolic metabolism is exemplified by the altered catabolism of glucose in tumour tissues 4. To meet the increased demand for biosynthetic precursors, cancer cells increase uptake of glucose and other nutrients, and shift overall metabolism from bioenergy (ATP) production and cell maintenance activities to anabolic processes that support cell mass accumulation and mitotic cell division 2, 3. Oncogenic signals drive constitutive cell growth and proliferation, and place heavy demands on the pathways responsible for providing the metabolic building blocks needed for the synthesis of proteins, nucleic acids, lipids and other macromolecules. Reprogramming of molecular and metabolic pathways involved in intermediate metabolism is now recognized as a hallmark of cancer 1. Treatment of cells with a glutaminase inhibitor phenocopies glutamine restriction, suggesting that these results will be relevant to the clinical development of glutamine metabolism inhibitors as anticancer agents. Activated mTORC1 elicits IL8 gene expression via the activation of an IRE1-JNK signalling cascade. The protein kinase, mTOR, is also colocalized with the lysosomal membrane clusters induced by glutamine deprivation, and inhibition of mTORC1 activity abolishes both endomembrane reorganization and IL-8 secretion. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates.
Glutamine deprivation-induced ER stress triggers colocalization of autophagosomes, lysosomes and the Golgi into a subcellular structure whose integrity is essential for IL-8 secretion. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, interleukin-8 (IL-8). The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance.
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