title: DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis.
abstract: Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP(-/-) mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ning
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Yun
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R-C
authors.initials: RC
authors.lastname: Pong
authors.affiliation: Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J-T
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: D
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: K
authors.initials: K
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002369:Castration; D045304:Cytochromes c / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D000077022:Survivin; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: C117749:Birc5 protein, mouse; C561450:Dab2ip protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000077022:Survivin; D020703:ras GTPase-Activating Proteins; D045304:Cytochromes c