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Research Paper

Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells

Implications for preventing chemotherapy resistance

, , , , , , & show all
Pages 1085-1097 | Received 28 Sep 2011, Accepted 07 Nov 2011, Published online: 15 Dec 2011

References

  • DeBerardinis RJ, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010; 29:313 - 324; PMID: 19881548; http://dx.doi.org/10.1038/onc.2009.358
  • Bode BP, Fuchs BC, Hurley BP, Conroy JL, Suetterlin JE, Tanabe KK, et al. Molecular and functional analysis of glutamine uptake in human hepatoma and liver-derived cells. Am J Physiol Gastrointest Liver Physiol 2002; 283:G1062 - G1073; PMID: 12381519
  • Eagle H. Nutrition needs of mammalian cells in tissue culture. Science 1955; 122:501 - 514; PMID: 13255879; http://dx.doi.org/10.1126/science.122.3168.501
  • Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458:762 - 765; PMID: 19219026; http://dx.doi.org/10.1038/nature07823
  • DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 2007; 104:19345 - 19350; PMID: 18032601; http://dx.doi.org/10.1073/pnas.0709747104
  • Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal 2010; 3:ra31; PMID: 20424262; http://dx.doi.org/10.1126/scisignal.2000911
  • Mariño G, Kroemer G. Ammonia: a diffusible factor released by proliferating cells that induces autophagy. Sci Signal 2010; 3:pe19; PMID: 20516476; http://dx.doi.org/10.1126/scisignal.3124pe19
  • Holroyde CP, Skutches CL, Boden G, Reichard GA. Glucose metabolism in cachectic patients with colorectal cancer. Cancer Res 1984; 44:5910 - 5913; PMID: 6388829
  • Tayek JA. A review of cancer cachexia and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr 1992; 11:445 - 456; PMID: 1506607
  • Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008; 118:3930 - 3942; PMID: 19033663
  • Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 2010; 9:3256 - 3276; PMID: 20814239; http://dx.doi.org/10.4161/cc.9.16.12553
  • Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle 2010; 9:3515 - 3533; PMID: 20855962; http://dx.doi.org/10.4161/cc.9.17.12928
  • Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 2006; 66:632 - 637; PMID: 16423989; http://dx.doi.org/10.1158/0008-5472.CAN-05-3260
  • Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009; 8:3984 - 4001; PMID: 19923890; http://dx.doi.org/10.4161/cc.8.23.10238
  • Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 2009; 174:2023 - 2034; PMID: 19411448; http://dx.doi.org/10.2353/ajpath.2009.080873
  • Qian N, Ueno T, Kawaguchi-Sakita N, Kawashima M, Yoshida N, Mikami Y, et al. Prognostic significance of tumor/stromal caveolin-1 expression in breast cancer patients. Cancer Sci 2011; 102:1590 - 1596; PMID: 21585620; http://dx.doi.org/10.1111/j.1349-7006.2011.01985.x
  • Koo JS, Park S, Kim SI, Lee S, Park BW. The impact of caveolin protein expression in tumor stroma on prognosis of breast cancer. Tumour Biol 2011; 32:787 - 799; PMID: 21584795; http://dx.doi.org/10.1007/s13277-011-0181-6
  • Di Vizio D, Morello M, Sotgia F, Pestell RG, Freeman MR, Lisanti MP. An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation. Cell Cycle 2009; 8:2420 - 2424; PMID: 19556867; http://dx.doi.org/10.4161/cc.8.15.9116
  • Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, et al. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle 2010; 9:3485 - 3505; PMID: 20861672; http://dx.doi.org/10.4161/cc.9.17.12721
  • Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, et al. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle 2010; 9:2423 - 2433; PMID: 20562526; http://dx.doi.org/10.4161/cc.9.12.12048
  • Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, et al. Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 2011; 10:1772 - 1783; PMID: 21558814; http://dx.doi.org/10.4161/cc.10.11.15659
  • Ogbureke KU, Fisher LW. SIBLING expression patterns in duct epithelia reflect the degree of metabolic activity. J Histochem Cytochem 2007; 55:403 - 409; PMID: 17210923; http://dx.doi.org/10.1369/jhc.6A7075.2007
  • Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, et al. Understanding the “lethal” drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor microenvironment. Cancer Biol Ther 2010; 10:537 - 542; PMID: 20861671; http://dx.doi.org/10.4161/cbt.10.6.13370
  • Martinez-Outschoorn UE, Lin Z, Ko YH, Goldberg AF, Flomenberg N, Wang C, et al. Understanding the metabolic basis of drug resistance: Therapeutic induction of the Warburg effect kills cancer cells. Cell Cycle 2011; 10:2521 - 2528; PMID: 21768775; http://dx.doi.org/10.4161/cc.10.15.16584
  • Bröer S, Brookes N. Transfer of glutamine between astrocytes and neurons. J Neurochem 2001; 77:705 - 719; PMID: 11331400; http://dx.doi.org/10.1046/j.1471-4159.2001.00322.x
  • Waagepetersen HS, Sonnewald U, Schousboe A. Compartmentation of glutamine, glutamate, and GABA metabolism in neurons and astrocytes: functional implications. Neuroscientist 2003; 9:398 - 403; PMID: 14580123; http://dx.doi.org/10.1177/1073858403254006
  • Deitmer JW, Broer A, Broer S. Glutamine efflux from astrocytes is mediated by multiple pathways. J Neurochem 2003; 87:127 - 135; PMID: 12969260; http://dx.doi.org/10.1046/j.1471-4159.2003.01981.x
  • Deitmer JW. Strategies for metabolic exchange between glial cells and neurons. Respir Physiol 2001; 129:71 - 81; PMID: 11738647; http://dx.doi.org/10.1016/S0034-5687(01)00283-3
  • Bacci A, Sancini G, Verderio C, Armano S, Pravettoni E, Fesce R, et al. Block of glutamate-glutamine cycle between astrocytes and neurons inhibits epileptiform activity in hippocampus. J Neurophysiol 2002; 88:2302 - 2310; PMID: 12424271; http://dx.doi.org/10.1152/jn.00665.2001
  • Parry-Billings M, Leighton B, Dimitriadis GD, Curi R, Bond J, Bevan S, et al. The effect of tumour bearing on skeletal muscle glutamine metabolism. Int J Biochem 1991; 23:933 - 937; PMID: 1773899; http://dx.doi.org/10.1016/0020-711X(91)90082-X
  • Chen MK, Espat NJ, Bland KI, Copeland EM 3rd, Souba WW. Influence of progressive tumor growth on glutamine metabolism in skeletal muscle and kidney. Ann Surg 1993; 217:655 - 666; discussion 66–7 PMID: 8099476; http://dx.doi.org/10.1097/00000658-199306000-00007
  • Szeliga M, Obara-Michlewska M. Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem Int 2009; 55:71 - 75; PMID: 19428809; http://dx.doi.org/10.1016/j.neuint.2009.01.008
  • Knox WE, Horowitz ML, Friedell GH. The proportionality of glutaminase content to growth rate and morphology of rat neoplasms. Cancer Res 1969; 29:669 - 680; PMID: 5251291
  • Linder-Horowitz M, Knox WE, Morris HP. Glutaminase activities and growth rates of rat hepatomas. Cancer Res 1969; 29:1195 - 1199; PMID: 4307782
  • Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 2010; 18:207 - 219; PMID: 20832749; http://dx.doi.org/10.1016/j.ccr.2010.08.009
  • Matsuno T, Goto I. Glutaminase and glutamine synthetase activities in human cirrhotic liver and hepatocellular carcinoma. Cancer Res 1992; 52:1192 - 1194; PMID: 1346587
  • Dal Bello B, Rosa L, Campanini N, Tinelli C, Torello Viera F, D'Ambrosio G, et al. Glutamine synthetase immunostaining correlates with pathologic features of hepatocellular carcinoma and better survival after radio-frequency thermal ablation. Clin Cancer Res 2010; 16:2157 - 2166; PMID: 20233882; http://dx.doi.org/10.1158/1078-0432.CCR-09-1978
  • Bai G, Rama Rao KV, Murthy CR, Panickar KS, Jayakumar AR, Norenberg MD. Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res 2001; 66:981 - 991; PMID: 11746427; http://dx.doi.org/10.1002/jnr.10056
  • Murthy CR, Rama Rao KV, Bai G, Norenberg MD. Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 2001; 66:282 - 288; PMID: 11592125; http://dx.doi.org/10.1002/jnr.1222
  • Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Lisanti MP. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 2011; 13:213; PMID: 21867571; http://dx.doi.org/10.1186/bcr2892
  • Pavlides S, Vera I, Gandara R, Sneddon S, Pestell R, Mercier I, et al. Warburg meets autophagy: cancer associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy and aerobic glycolysis. Antioxid Redox Signal 2011; In press PMID: 21883043; http://dx.doi.org/10.1089/ars.2011.4243
  • Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006; 126:107 - 120; PMID: 16839880; http://dx.doi.org/10.1016/j.cell.2006.05.036
  • Bensaad K, Cheung EC, Vousden KH. Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 2009; 28:3015 - 3026; PMID: 19713938; http://dx.doi.org/10.1038/emboj.2009.242
  • Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008; 105:18782 - 18787; PMID: 19033189; http://dx.doi.org/10.1073/pnas.0810199105
  • Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 2007; 178:93 - 105; PMID: 17606868; http://dx.doi.org/10.1083/jcb.200703099
  • Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 1987; 235:1492 - 1495; PMID: 3103217; http://dx.doi.org/10.1126/science.3103217