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Molecular and Cellular Biology, January 2004, p. 924-935, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.924-935.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

HOXA5-Induced Apoptosis in Breast Cancer Cells Is Mediated by Caspases 2 and 8

Hexin Chen, Seung Chung, and Saraswati Sukumar*

Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231

Received 2 June 2003/ Returned for modification 10 July 2003/ Accepted 6 October 2003

HOXA5 is a transcriptional factor whose expression is lost in more than 60% of breast carcinomas. Our previous work demonstrated that the overexpression of HOXA5 in MCF7 cells resulted in cell death through a p53-dependent apoptotic pathway. To determine whether p53-independent apoptotic pathways are involved in HOXA5-induced cell death, we engineered a p53-mutant breast cancer cell line, Hs578T, to inducibly express HOXA5. Induction of HOXA5 expression led to cell death with features typical of apoptosis within 24 h, and the expression levels of mutant p53 and its target genes either decreased or remained unchanged. To decipher apoptotic pathways, the HOXA5-expressing cells were treated with a variety of apoptotic inhibitors. Besides a general caspase inhibitor, caspase 2- and 8-specific inhibitors largely abolished HOXA5-induced apoptosis, whereas caspase 1-, 3-, 6-, and 9-specific inhibitors had no significant effects. Western blot analysis further confirmed that caspases 2 and 8 were activated after the induction of HOXA5 expression. Further, several small interfering RNAs which specifically silenced caspase 2 and caspase 8 expression significantly blocked HOXA5-induced apoptosis. HOXA5 expression could also sensitize cells to tumor necrosis factor alpha-induced apoptosis by at least 100-fold. These results indicate that expression of HOXA5 can induce apoptosis through an apoptotic mechanism mediated by caspases 2 and 8.

* Corresponding author. Mailing address: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St., CRB 410, Baltimore, MD 21231-1000. Phone: (410) 614-2479. Fax: (410) 614-4073. E-mail: sukumsa{at}jhmi.edu.

Molecular and Cellular Biology, January 2004, p. 924-935, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.924-935.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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