title: Glutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion.
abstract: The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. 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). 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. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates. 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. Activated mTORC1 elicits IL8 gene expression via the activation of an IRE1-JNK signalling cascade. 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.
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Naval P
authors.initials: NP
authors.lastname: Shanware
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bray
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Christina H
authors.initials: CH
authors.lastname: Eng
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Follettie
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Myers
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10777 Science Center Drive, La Jolla, California 92121, USA.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, 10777 Science Center Drive, La Jolla, California 92121, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
mesh_terms: D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D059865:Endoplasmic Reticulum Stress; D005973:Glutamine; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; D046912:Multiprotein Complexes; D005973:Glutamine; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4