Caspase-2 is involved in cell death induction by taxanes in breast cancer cells

Cancer Cell International

Jan Kovář¹  Iwao Ojima²  Ilaria Zanardi²  Julie Fidlerová¹  Jan Šrámek¹  Vlasta Němcová-Fürstová¹  Dana Kopperová¹  Kamila Balušíková¹  Michael Jelínek¹ 

[1] Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic;Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA

关键词: Breast cancer cells;    Taxanes;    Cell death;    Caspase-2;   

Others  :  793889
DOI  :  10.1186/1475-2867-13-42

 received in 2013-01-18, accepted in 2013-05-01,  发布年份 2013

【 摘 要 】

Background

We studied the role of caspase-2 in apoptosis induction by taxanes (paclitaxel, novel taxane SB-T-1216) in breast cancer cells using SK-BR-3 (nonfunctional p53, functional caspase-3) and MCF-7 (functional p53, nonfunctional caspase-3) cell lines.

Results

Both taxanes induced apoptosis in SK-BR-3 as well as MCF-7 cells. Caspase-2 activity in SK-BR-3 cells increased approximately 15-fold within 48 h after the application of both taxanes at the death-inducing concentration (100 nM). In MCF-7 cells, caspase-2 activity increased approximately 11-fold within 60 h after the application of taxanes (300 nM). Caspase-2 activation was confirmed by decreasing levels of procaspase-2, increasing levels of cleaved caspase-2 and the cleavage of caspase-2 substrate golgin-160. The inhibition of caspase-2 expression using siRNA increased the number of surviving cells more than 2-fold in MCF-7 cells, and at least 4-fold in SK-BR-3 cells, 96 h after the application of death-inducing concentration of taxanes. The inhibition of caspase-2 expression also resulted in decreased cleavage of initiator caspases (caspase-8, caspase-9) as well as executioner caspases (caspase-3, caspase-7) in both cell lines after the application of taxanes. In control cells, caspase-2 seemed to be mainly localized in the nucleus. After the application of taxanes, it was released from the nucleus to the cytosol, due to the long-term disintegration of the nuclear envelope, in both cell lines. Taxane application led to some formation of PIDDosome complex in both cell lines within 24 h after the application. After taxane application, p21^WAF1/CIP1 expression was only induced in MCF-7 cells with functional p53. However, taxane application did not result in a significant increase of PIDD expression in either SK-BR-3 or MCF-7 cells. The inhibition of RAIDD expression using siRNA did not affect the number of surviving SK-BR-3 and MCF-7 cells after taxane application at all.

Conclusion

Caspase-2 is required, at least partially, for apoptosis induction by taxanes in tested breast cancer cells. We suggest that caspase-2 plays the role of an apical caspase in these cells. Caspase-2 seems to be activated via other mechanism than PIDDosome formation. It follows the release of caspase-2 from the nucleus to the cytosol.

【 授权许可】

   
2013 Jelínek et al.; licensee BioMed Central Ltd.

【 图 表 】

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