Oncotarget

Research Papers:

Sulforaphane-induced apoptosis involves the type 1 IP3 receptor

Sona Hudecova _, Jana Markova, Veronika Simko, Lucia Csaderova, Tibor Stracina, Marta Sirova, Michaela Fojtu, Eliska Svastova, Paulina Gronesova, Michal Pastorek, Marie Novakova, Dana Cholujova, Juraj Kopacek, Silvia Pastorekova, Jan Sedlak and Olga Krizanova

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Oncotarget. 2016; 7:61403-61418. https://doi.org/10.18632/oncotarget.8968

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Abstract

Sona Hudecova1, Jana Markova1, Veronika Simko2, Lucia Csaderova2, Tibor Stracina3, Marta Sirova1, Michaela Fojtu3, Eliska Svastova2, Paulina Gronesova4, Michal Pastorek4, Marie Novakova3, Dana Cholujova4, Juraj Kopacek2, Silvia Pastorekova2, Jan Sedlak4, Olga Krizanova1

1Institute of Clinical and Translational Research, Biomedical Research Center, SAS, Bratislava, Slovakia

2Institute of Virology, Biomedical Research Center, SAS, Bratislava, Slovakia

3Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

4Cancer Research Institute, Biomedical Research Center, SAS, Bratislava, Slovakia

Correspondence to:

Olga Krizanova, email: [email protected]

Keywords: type 1 IP3 receptor, sulforaphane, apoptosis, NRF2, nude mice

Received: April 20, 2015     Accepted: April 15, 2016     Published: August 01, 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.


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