title: RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis.
abstract: Cancer cells are more susceptible to chemotherapeutic agent-induced apoptosis than their normal counterparts. Although it has been demonstrated that the increased sensitivity results from deregulation of oncoproteins during cancer development (Evan, G. I., and Vousden, K. H. (2001) Nature 411, 342-348; Green, D. R., and Evan, G. I. (2002) Cancer Cell 1, 19-30), little is known about the signaling pathways leading to changes in the apoptotic threshold in cancer cells. Here we show that low RKIP expression levels in tumorigenic human prostate and breast cancer cells are rapidly induced upon chemotherapeutic drug treatment, sensitizing the cells to apoptosis. We show that the maximal RKIP expression correlates perfectly with the onset of apoptosis. In cancer cells resistant to DNA-damaging agents, treatment with the drugs does not up-regulate RKIP expression. However, ectopic expression of RKIP resensitizes DNA-damaging agent-resistant cells to undergo apoptosis. This sensitization can be reversed by up-regulation of survival pathways. Down-regulation of endogenous RKIP by expression of antisense and small interfering RNA (siRNA) confers resistance on sensitive cancer cells to anticancer drug-induced apoptosis. Our studies suggest that RKIP may represent a novel effector of signal transduction pathways leading to apoptosis and a prognostic marker of the pathogenesis of human cancer cells and tumors after treatment with clinically relevant chemotherapeutic drugs.
authors.affiliation: Department of Medicine, Brown University and Rhode Island Hospital, Providence, Rhode Island 02903, USA.
authors.forename: Devasis
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Yin
authors.initials: Y
authors.lastname: Bai
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Sandy
authors.initials: S
authors.lastname: Beach
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mott
authors.forename: Rajat
authors.initials: R
authors.lastname: Roy
authors.forename: Corey
authors.initials: C
authors.lastname: Braastad
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Asok
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: James
authors.initials: J
authors.lastname: Darnowski
authors.forename: Panayotis
authors.initials: P
authors.lastname: Pantazis
authors.forename: James
authors.initials: J
authors.lastname: Wyche
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kitagwa
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: John M
authors.initials: JM
authors.lastname: Sedivy
authors.forename: Kam C
authors.initials: KC
authors.lastname: Yeung
mesh_terms: D000727:Androgen-Binding Protein / Q000502:physiology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D015536:Down-Regulation; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D049488:Phosphatidylethanolamine Binding Protein; D010957:Plasmids / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000473:pathology*; D016372:RNA, Antisense / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000727:Androgen-Binding Protein; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D004247:DNA