title: Contrasting effects of glutamine deprivation on apoptosis induced by conventionally used anticancer drugs.
abstract: Tumor cells dependence on glutamine offers a rationale for their elimination via targeting of glutamine metabolism. The aim of this work was to investigate how glutamine deprivation affects the cellular response to conventionally used anticancer drugs. To answer this question, neuroblastoma cells were pre-incubated in a glutamine-free medium and treated with cisplatin or etoposide. Obtained results revealed that glutamine withdrawal affected cellular response to therapeutic drugs in a different manner. Glutamine deprivation suppressed etoposide-induced, but markedly stimulated cisplatin-induced apoptosis. Suppression of etoposide-induced cell death correlated with a downregulation of p53 expression, which, among other functions, regulates the expression of death receptor 5, one of the activators of caspase-8. In contrast, stimulation of cisplatin-induced cell death involved reactive oxygen species-mediated downregulation of FLIP-S, an inhibitor of caspase-8. As a result, the activity of caspase-8 was stimulated causing cleavage of the pro-apoptotic protein Bid, which is involved in the permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic factors, such as cytochrome c from mitochondria. Thus, suppression of glutamine metabolism can sensitize tumor cells to treatment and could be utilized for anti-cancer therapy. However, it should be done cautiously, since adverse effects may occur when combined with an inappropriate therapeutic drug.
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden.
authors.forename: Kadri
authors.initials: K
authors.lastname: Valter
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; College of Veterinary Medicine, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Kruspig
authors.affiliation: MV Lomonosov Moscow State University, 119991 Moscow, Russia.
authors.forename: Polina
authors.initials: P
authors.lastname: Maximchik
authors.affiliation: College of Veterinary Medicine, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
authors.forename: Hengmin
authors.initials: H
authors.lastname: Cui
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; MV Lomonosov Moscow State University, 119991 Moscow, Russia.
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; MV Lomonosov Moscow State University, 119991 Moscow, Russia. Electronic address: Vladimir.Gogvadze@ki.se.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry; D045304:Cytochromes c / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000172:deficiency*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D003470:Culture Media; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D005047:Etoposide; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D002945:Cisplatin
keywords: Apoptosis; Caspases; Glutamine; Mitochondria; Reactive oxygen species