title: Sulforaphane-induced apoptosis involves the type 1 IP3 receptor.
abstract: In this study we show that anti-tumor effect of sulforaphane (SFN) is partially realized through the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1). This effect was verified in vitro on three different stable cell lines and also in vivo on the model of nude mice with developed tumors. Early response (6 hours) of A2780 ovarian carcinoma cells to SFN treatment involves generation of mitochondrial ROS and increased transcription of NRF2 and its downstream regulated genes including heme oxygenase 1, NAD(P)H:quinine oxidoreductase 1, and KLF9. Prolonged SFN treatment (24 hours) upregulated expression of NRF2 and IP3R1. SFN induces a time-dependent phosphorylation wave of HSP27. Use of IP3R inhibitor Xestospongin C (Xest) attenuates both SFN-induced apoptosis and the level of NRF2 protein expression. In addition, Xest partially attenuates anti-tumor effect of SFN in vivo. SFN-induced apoptosis is completely inhibited by silencing of IP3R1 gene but only partially blocked by silencing of NRF2; silencing of IP3R2 and IP3R3 had no effect on these cells. Xest inhibitor does not significantly modify SFN-induced increase in the rapid activity of ARE and AP1 responsive elements. We found that Xest effectively reverses the SFN-dependent increase of nuclear content and decrease of reticular calcium content. In addition, immunofluorescent staining with IP3R1 antibody revealed that SFN treatment induces translocation of IP3R1 to the nucleus. Our results clearly show that IP3R1 is involved in SFN-induced apoptosis through the depletion of reticular calcium and modulation of transcription factors through nuclear calcium up-regulation.
authors.affiliation: Institute of Clinical and Translational Research, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Sona
authors.initials: S
authors.lastname: Hudecova
authors.affiliation: Institute of Clinical and Translational Research, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Jana
authors.initials: J
authors.lastname: Markova
authors.affiliation: Institute of Virology, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Simko
authors.affiliation: Institute of Virology, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Csaderova
authors.affiliation: Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Tibor
authors.initials: T
authors.lastname: Stracina
authors.affiliation: Institute of Clinical and Translational Research, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Marta
authors.initials: M
authors.lastname: Sirova
authors.affiliation: Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fojtu
authors.affiliation: Institute of Virology, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Eliska
authors.initials: E
authors.lastname: Svastova
authors.affiliation: Cancer Research Institute, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Paulina
authors.initials: P
authors.lastname: Gronesova
authors.affiliation: Cancer Research Institute, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Pastorek
authors.affiliation: Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Novakova
authors.affiliation: Cancer Research Institute, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Dana
authors.initials: D
authors.lastname: Cholujova
authors.affiliation: Institute of Virology, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kopacek
authors.affiliation: Institute of Virology, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.affiliation: Cancer Research Institute, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Jan
authors.initials: J
authors.lastname: Sedlak
authors.affiliation: Institute of Clinical and Translational Research, Biomedical Research Center, SAS, Bratislava, Slovakia.
authors.forename: Olga
authors.initials: O
authors.lastname: Krizanova
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D061745:Antioxidant Response Elements; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017879:Isothiocyanates / Q000494:pharmacology* / Q000627:therapeutic use; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013454:Sulfoxides; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017879:Isothiocyanates; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D047028:Macrocyclic Compounds; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010080:Oxazoles; D017382:Reactive Oxygen Species; D013454:Sulfoxides; C511704:xestospongin C; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C016766:sulforaphane; D002118:Calcium
keywords: NRF2; apoptosis; nude mice; sulforaphane; type 1 IP3 receptor