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Sulforaphane-induced apoptosis involves the type 1 IP3 receptor.
- Source :
-
Oncotarget [Oncotarget] 2016 Sep 20; Vol. 7 (38), pp. 61403-61418. - Publication Year :
- 2016
-
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.<br />Competing Interests: The authors declare that they have no conflicts of interest.
- Subjects :
- Animals
Anticarcinogenic Agents therapeutic use
Antioxidant Response Elements
Cell Line, Tumor
Cell Nucleus metabolism
Endoplasmic Reticulum metabolism
Female
Heme Oxygenase-1 metabolism
Humans
Inositol 1,4,5-Trisphosphate Receptors antagonists & inhibitors
Isothiocyanates therapeutic use
Kruppel-Like Transcription Factors metabolism
Macrocyclic Compounds pharmacology
Mice
Mice, Nude
Mitochondria drug effects
Mitochondria metabolism
NAD(P)H Dehydrogenase (Quinone) metabolism
Ovarian Neoplasms drug therapy
Ovarian Neoplasms pathology
Oxazoles pharmacology
Oxidative Stress drug effects
Reactive Oxygen Species metabolism
Sulfoxides
Transcriptional Activation drug effects
Up-Regulation
Xenograft Model Antitumor Assays
Anticarcinogenic Agents pharmacology
Apoptosis drug effects
Calcium metabolism
Inositol 1,4,5-Trisphosphate Receptors metabolism
Isothiocyanates pharmacology
NF-E2-Related Factor 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 38
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27528021
- Full Text :
- https://doi.org/10.18632/oncotarget.8968