p53-Independent apoptosis by benzyl isothiocyanate in human breast cancer cells is mediated by suppression of XIAP expression.

We have shown previously that cruciferous vegetable constituent benzyl isothiocyanate (BITC) suppresses viability of cultured MCF-7 and MDA-MB-231 human breast cancer cells and retards mammary cancer development in MMTV-neu mice by causing apoptosis, but the mechanism of cell death is not fully understood. We now show that whereas p53 is dispensable for BITC-induced cell death, proapoptotic response to this promising chemopreventive agent is mediated by suppression of X-linked inhibitor of apoptosis (XIAP) protein expression. The BITC treatment increased levels of total and Ser(15)-phosphorylated p53 protein in MCF-7 cells, but the proapoptotic response to this agent was maintained even after knockdown of the p53 protein level. Exposure of MCF-7 and MDA-MB-231 cells to BITC resulted in a marked decrease in protein level of XIAP as early as 8 hours after treatment. Ectopic expression of XIAP conferred statistically significant protection against BITC-mediated cytoplasmic histone-associated apoptotic DNA fragmentation in both cell lines. Moreover, inhibition of MDA-MB-231 cell growth in vivo in female athymic mice by BITC administration correlated with a modest but statistically significant decrease in XIAP protein level in the tumor xenograft. The BITC treatment also resulted in induction as well as nuclear translocation of survivin only in the MCF-7 cells. The BITC-induced apoptosis was modestly but statistically significantly augmented by RNA interference of survivin in MCF-7 cells. In conclusion, the present study provides novel insight into the molecular circuitry of BITC-induced apoptosis to indicate suppression of XIAP expression as a critical mediator of this process.

Kim SH ，Singh SV 《-》

Critical role of p53 upregulated modulator of apoptosis in benzyl isothiocyanate-induced apoptotic cell death.

Antony ML ，Kim SH ，Singh SV 《-》

Benzyl isothiocyanate inhibits epithelial-mesenchymal transition in cultured and xenografted human breast cancer cells.

Sehrawat A ，Singh SV 《-》

Benzyl isothiocyanate causes FoxO1-mediated autophagic death in human breast cancer cells.

Xiao D ，Bommareddy A ，Kim SH ，Sehrawat A ，Hahm ER ，Singh SV ... -  《PLoS One》

Noscapine induced apoptosis via downregulation of survivin in human neuroblastoma cells having wild type or null p53.

Li S ，He J ，Li S ，Cao G ，Tang S ，Tong Q ，Joshi HC ... -  《-》