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Expression of Siva-1 Protein or Its Putative Amphipathic Helical Region Enhances Cisplatin-Induced Apoptosis in Breast Cancer Cells: Effect of Elevated Levels of BCL-2

¹ Department of Microbiology and Immunology, University of Illinois at Chicago; and ² Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois

Requests for reprints: Prasad V.S. Kanteti, Department of Microbiology and Immunology, University of Illinois at Chicago, Room 820, 835 South Wolcott Avenue, Chicago, IL 60612. Phone: 312-413-3423; Fax: 312-996-6415; E-mail: kanteti{at}uic.edu.

cis-Diaminedichloroplatinum (II) (cisplatin) is routinely used to treat various types of cancers; however, a significant number develop resistance. One of the underlying factors that contribute to cisplatin resistance is the elevated level of BCL-2 and/or BCL-XL, which promotes cell survival. A potential method of overcoming such resistance is to use a potentiator that is capable of neutralizing the antiapoptotic effects of BCL-2/BCL-XL, such as Siva-1. We previously cloned the proapoptotic protein Siva-1 and showed a possible role for it in both extrinsic and intrinsic apoptosis. Using an adenovirus-based expression system, we now show that Siva-1 can synergize with cisplatin in inducing apoptosis in MCF7 and MDA-MB-231 breast cancer cells. In an anchorage-independent clonogenicity assay, MCF7/caspase-3 cells stably expressing Siva-1, but not the control cells, showed a dramatic decrease in the number of colonies formed on one-time cisplatin treatment. Further, we show that the unique putative amphipathic helical region (SAH) in Siva-1 (amino acid residues 36-55) is necessary and sufficient for the observed enhancement in cisplatin-induced apoptosis by Siva-1. Although cisplatin treatment results in significant elevation in the expression of Fas ligand and intracellular p21 levels, expression of Siva-1 has no additional benefit. Instead, the enhancement in apoptosis seems to be due to activation of intrinsic pathway that involves caspase-9 activation. Moreover, Siva-1 augments cisplatin-mediated cell death in MCF7 cells stably expressing BCL-2. We therefore propose that Siva-1 or its SAH region can be used as a potentiator of cisplatin-based chemotherapy.