title: The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis.
abstract: Treatment resistance, the major challenge in the management of advanced prostate cancer, is in part based on resistance to apoptosis. The Inhibitor of Apoptosis (IAP) family is thought to play key roles in survival and drug resistance of cancer via inhibition of apoptosis. Of the IAP family members, cIAP1, cIAP2, XIAP and survivin are known to be up-regulated in prostate cancer. BIRC6, a much less studied IAP member, was recently shown to be elevated in castration-resistant prostate cancer (CRPC). In the present study, we showed a correlation between elevated BIRC6 expression in clinical prostate cancer specimens and poor patient prognostic factors, as well as co-upregulation of certain IAP members. In view of this, we designed antisense oligonucleotides that simultaneously target BIRC6 and another co-upregulated IAP member (dASOs). Two dASOs, targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cells proliferation, exceeding that obtained with single BIRC6 targeting. The growth inhibition was associated with increased apoptosis, cell cycle arrest and suppression of NFkB activation. Moreover, treatment with both dASOs led to significantly lower viable tumor volume in vivo, without major host toxicity. This study shows that BIRC6-based dual IAP-targeting ASOs represent potential novel therapeutic agents against advanced prostate cancer.
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Sze Ue Iris
authors: SU
authors: Luk
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Hui
authors: H
authors: Xue
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Hongwei
authors: H
authors: Cheng
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Dong
authors: D
authors: Lin
authors: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Peter W
authors: PW
authors: Gout
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada.
authors: Ladan
authors: L
authors: Fazli
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada.
authors: Colin C
authors: CC
authors: Collins
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada.
authors: Martin E
authors: ME
authors: Gleave
authors: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, the University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Yuzhuo
authors: Y
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011897:Random Allocation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C401541:BIRC6 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering