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.
- MeSH
- aktivace transkripce účinky léků MeSH
- antikarcinogenní látky farmakologie terapeutické užití MeSH
- antioxidační responzivní elementy MeSH
- apoptóza účinky léků MeSH
- buněčné jádro metabolismus MeSH
- endoplazmatické retikulum metabolismus MeSH
- faktor 2 související s NF-E2 metabolismus MeSH
- hemoxygenasa-1 metabolismus MeSH
- inositol-1,4,5-trisfosfát - receptory antagonisté a inhibitory metabolismus MeSH
- isothiokyanatany farmakologie terapeutické užití MeSH
- lidé MeSH
- makrocyklické sloučeniny farmakologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- myši nahé MeSH
- myši MeSH
- NAD(P)H dehydrogenasa (chinon) metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků farmakoterapie patologie MeSH
- oxazoly farmakologie MeSH
- oxidační stres účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- transkripční faktory Krüppel-like metabolismus MeSH
- upregulace MeSH
- vápník metabolismus MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
