title: Arginine deprivation induces endoplasmic reticulum stress in human solid cancer cells.
abstract: Deprivation for the single amino acid arginine is a rapidly developing metabolic anticancer therapy, which allows growth control in a number of highly malignant tumors. Here we report that one of the responses of human solid cancer cells to arginine starvation is the induction of prolonged endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Systematic study of two colorectal carcinoma HCT-116 and HT29, glioblastoma U251 MG and ovarian carcinoma SKOV3 cell lines revealed, however, that the ER stress triggered by the absence of arginine does not result in massive apoptosis despite a profound upregulation of the proapoptotic gene CHOP. Instead, Akt- and MAPK-dependent pathways were activated which may counteract proapoptotic signaling. Treatment with DMSO as a disaggregating agent or with cycloheximide to block protein synthesis reduced ER stress evoked by arginine deprivation. On the other hand, ER stress and apoptosis induction in arginine-starved cells could be critically augmented by the arginine analog of plant origin canavanine, but not by the classic ER stress inducer tunicamycin. Our data suggest that canavanine treatment applied under the lack of arginine may enhance the efficacy of arginine deprivation-based anticancer therapy.
authors.affiliation: Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine. Electronic address: bobakyaroslav@gmail.com.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Bobak
authors.affiliation: Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address: kurlishchukyuliya@gmail.com.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Kurlishchuk
authors.affiliation: Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address: b.vynnytskamyronovska@gmail.com.
authors.forename: Bozhena
authors.initials: B
authors.lastname: Vynnytska-Myronovska
authors.affiliation: Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine. Electronic address: olesia.hr@gmail.com.
authors.forename: Olesia
authors.initials: O
authors.lastname: Grydzuk
authors.affiliation: Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine. Electronic address: galinash1977@mail.ru.
authors.forename: Galyna
authors.initials: G
authors.lastname: Shuvayeva
authors.affiliation: Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur Str. 3, 02-093 Warsaw, Poland. Electronic address: jolanta@nencki.gov.pl.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Redowicz
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Fetscherstr. 74, 01307 Dresden, Germany; Department of Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: leoni.kunz-schughart@oncoray.de.
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.affiliation: Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine. Electronic address: stasyk@cellbiol.lviv.ua.
authors.forename: Oleh
authors.initials: O
authors.lastname: Stasyk
mesh_terms: D001120:Arginine / Q000172:deficiency*; D002172:Canavanine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003470:Culture Media / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D003470:Culture Media; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C486654:EDEM1 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C053387:endoplasmin; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D002172:Canavanine; D001120:Arginine; D003513:Cycloheximide; D051057:Proto-Oncogene Proteins c-akt; D004121:Dimethyl Sulfoxide
keywords: Arginine deprivation; Canavanine; ER stress; Metabolic anticancer therapy