Identification of a novel pathway that selectively modulates apoptosis of breast cancer cells.
Expression of the nuclear receptor interacting factor 3 (NRIF3) coregulator in a wide variety of breast cancer cells selectively leads to rapid caspase-2-dependent apoptotic cell death. A novel death domain (DD1) was mapped to a 30-amino acid region of NRIF3. Because the cytotoxicity of NRIF3 and DD1 seems to be cell type-specific, these studies suggest that breast cancer cells contain a novel "death switch" that can be specifically modulated by NRIF3 or DD1. Using an MCF-7 cell cDNA library in a yeast two-hybrid screen, we cloned a factor that mediates apoptosis by DD1 and refer to this factor as DD1-interacting factor-1 (DIF-1). DIF-1 is a transcriptional repressor that mediates its effect through SirT1, and this repression is attenuated by the binding of NRIF3/DD1. DIF-1 expression rescues breast cancer cells from NRIF3/DD1-induced apoptosis. Small interfering RNA (siRNA) knockdown of DIF-1 selectively leads to apoptosis of breast cancer cells, further suggesting that DIF-1 plays a key role in NRIF3/DD1-mediated apoptosis. A protein kinase A inhibitor (H89) also elicits apoptosis of breast cancer cells but not of the other cell types examined, and DIF-1 also protects these cells from H89-mediated apoptosis. In addition, H89 incubation results in a rapid increase in NRIF3 levels and siRNA knockdown of NRIF3 protects breast cancer cells from H89-mediated apoptosis. Our results indicate that DIF-1 plays a key role in breast cancer cell survival and further characterizing this pathway may provide important insights into developing novel therapies to selectively target breast cancer cells for apoptosis.
Tinnikov
Alexander A
AA
Department of Pharmacology and Medicine, The Entertainment Industry Foundation Research Laboratory, New York University School of Medicine, New York, New York 10016, USA.
Yeung
Kay T
KT
Das
Sharmistha
S
Samuels
Herbert H
HH
D053959:Alpha-Amanitin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D053143:Caspase 2 / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005260:Female; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors
D053959:Alpha-Amanitin; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C475082:IRF2BP2 protein, human; C403295:ITGB3BP protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D053143:Caspase 2