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The Nuclear Receptor Interacting Factor-3 Transcriptional Coregulator Mediates Rapid Apoptosis in Breast Cancer Cells through Direct and Bystander-Mediated Events

Departments of ¹ Pharmacology and ² Medicine, New York University School of Medicine, and ³ Department of Basic Sciences, College of Dentistry, New York University, New York, New York

Requests for reprints: Herbert H. Samuels, Department of Pharmacology, MSB 424, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-6279; Fax: 212-263-7133; E-mail: herbert.samuels{at}med.nyu.edu.

We previously reported that amino acids 20 to 50 of nuclear receptor interacting factor-3 mediates rapid apoptosis in breast cancer cell lines but not in cells derived from other tissues. We refer to this short region as death domain-1 (DD1). Small interfering RNA studies indicated that DD1-mediated apoptosis is caspase-2 dependent. In this study, we examined DD1-mediated apoptosis in more detail and generated stable caspase-2 knockdown breast cancer cells. These cells are resistant to DD1-mediated apoptosis. Time-lapse movies suggested that DD1-mediated apoptosis also leads to a "bystander effect." We found that within 5 h of DD1 expression, breast cancer cells release a factor(s) into the medium that leads to apoptosis of naive breast cancer cells or DD1-resistant cells (e.g., HeLa). The DD1-expressing caspase-2 knockdown cells also release a factor(s) that kills other cells, indicating that this effect is not dependent on the apoptogenic process. The bystander effect seems dependent on the production of reactive oxygen species (ROS). These and other studies indicate that DD1 expression in breast cancer cells leads to at least two death signals: one involving the rapid production of ROS and/or other soluble factors that directly or indirectly leads to a bystander effect and a second caspase-2–dependent process that leads to apoptosis in cells in which DD1 is expressed. [Cancer Res 2007;67(4):1775–82]

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				Correction: Mechanisms of NRIF3-Mediated Apoptosis in Breast Cancer Cancer Res., May 1, 2007; 67(9): 4535 - 4535. [Full Text] [PDF]