title: Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer.
abstract: Prostate cancer is the second leading cause of cancer death in the United States and, thus far, there has been no effective therapy for the treatment of hormone-refractory disease. Recently, the androgen receptor (AR) has been shown to play a critical role in the development and progression of the disease. In this report, we showed that knocking down the AR protein level by a small interfering RNA (siRNA) approach resulted in a significant apoptotic cell death as evidenced by an increased annexin V binding, reduced mitochondrial potential, caspase-3/6 activation, and DFF45 and poly(ADP-ribose) polymerase cleavage. The apoptotic response was specifically observed in those siRNA-transfected cells that harbor a native AR gene. No cell death was found in the AR-null prostate cancer cell PC-3 or its subline that has been reconstituted with an exogenous AR gene, as well as two breast cancer cell lines that are AR positive. Moreover, in parallel with the siRNA-induced AR silencing, the antiapoptotic protein Bcl-xL was significantly reduced, which might account for the apoptotic cell death because ectopic enforced expression of Bcl-xL protein partially inhibited apoptosis after AR silencing. Taken together, our data showed that knocking down the AR protein level in prostate cancer cells leads to apoptosis by disrupting the Bcl-xL-mediated survival signal downstream of AR-dependent survival pathway.
authors.affiliation: Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.
authors.forename: Xinbo
authors.initials: X
authors.lastname: Liao
authors.forename: Siqing
authors.initials: S
authors.lastname: Tang
authors.forename: J Brantley
authors.initials: JB
authors.lastname: Thrasher
authors.forename: Tomas L
authors.initials: TL
authors.lastname: Griebling
authors.forename: Benyi
authors.initials: B
authors.lastname: Li
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein
chemical_list: D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D051020:bcl-X Protein; C109664:caspase-activated DNase inhibitor; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505514:CASP6 protein, human; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases