title: The mechanism of DAB2IP in chemoresistance of prostate cancer cells.
abstract: OBJECTIVE
  The docetaxel-based chemotherapy is the standard of care for castration-resistant prostate cancer (CRPC), inevitably, patients develop resistance and decease. Until now, the mechanism and predictive marker for chemoresistance are poorly understood.
  
  
  METHODS
  Immortalized normal prostate and cancer cell lines stably manipulated with different DAB2IP expression levels were used and treated with chemotherapeutic drugs commonly used in prostate cancer therapy. Cell proliferation was measured using MTT assay; Western blot, quantitative PCR, and luciferase reporter assays were used to analyze Clusterin gene regulation by DAB2IP. Immunohistochemical analysis was conducted for evaluating DAB2IP, Clusterin and Egr-1 expression in human prostate cancer tissue.
  
  
  RESULTS
  DAB2IP Knockdown (KD) cells exhibited resistance to several chemotherapeutic drugs, whereas increased DAB2IP in C4-2 cells restored the drug sensitivity. Parallel, DAB2IP KD cells exhibited higher expression of Clusterin, an antiapoptotic factor, whereas elevated DAB2IP in C4-2 cells decreased Clusterin expression. Functionally, knocking down Clusterin by short-hairpin RNA or antisense oligonucleotide OGX-011 decreased drug resistance, whereas overexpressing Clusterin in C4-2 D2 enhanced drug resistance. Mechanistically, DAB2IP blocked the cross-talk between Wnt/β-catenin and IGF-I signaling, leading to the suppression of Egr-1 that is responsible for Clusterin expression. A similar result was observed in the prostate of DAB2IP knockout animals. In addition, we observed a significantly inverse correlation between DAB2IP and Egr-1 or Clusterin expression from clinical tissue microarray.
  
  
  CONCLUSIONS
  This study unveils a new regulation of the Egr-1/Clusterin signaling network by DAB2IP. Loss of DAB2IP expression in CRPC cells signifies their chemoresistance. Clusterin is a key target for developing more effective CRPC therapy.
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.forename: Daxing
authors.initials: D
authors.lastname: Xie
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Zou
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Rey-Chen
authors.initials: RC
authors.lastname: Pong
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Dalin
authors.initials: D
authors.lastname: He
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051152:Clusterin / Q000235:genetics; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051152:Clusterin; C462952:DAB2IP protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D043823:Taxoids; D020703:ras GTPase-Activating Proteins; D000077143:Docetaxel