The mechanism of DAB2IP in chemoresistance of prostate cancer cells

Kaijie Wu, Daxing Xie, Yonglong Zou, Tingting Zhang, Rey Chen Pong, Guanghua Xiao, Ladan Fazli, Martin Gleave, Dalin He, David A. Boothman, Jer Tsong Hsieh

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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 D2enhanced 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.

Original languageEnglish (US)
Pages (from-to)4740-4749
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number17
DOIs
StatePublished - Sep 1 2013

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Clusterin
Prostatic Neoplasms
Castration
docetaxel
Drug Resistance
Pharmaceutical Preparations
Catenins
Antisense Oligonucleotides
Standard of Care
Luciferases
Insulin-Like Growth Factor I
Small Interfering RNA
Prostate
Research Design
Western Blotting
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The mechanism of DAB2IP in chemoresistance of prostate cancer cells. / Wu, Kaijie; Xie, Daxing; Zou, Yonglong; Zhang, Tingting; Pong, Rey Chen; Xiao, Guanghua; Fazli, Ladan; Gleave, Martin; He, Dalin; Boothman, David A.; Hsieh, Jer Tsong.

In: Clinical Cancer Research, Vol. 19, No. 17, 01.09.2013, p. 4740-4749.

Research output: Contribution to journalArticle

Wu, K, Xie, D, Zou, Y, Zhang, T, Pong, RC, Xiao, G, Fazli, L, Gleave, M, He, D, Boothman, DA & Hsieh, JT 2013, 'The mechanism of DAB2IP in chemoresistance of prostate cancer cells', Clinical Cancer Research, vol. 19, no. 17, pp. 4740-4749. https://doi.org/10.1158/1078-0432.CCR-13-0954
Wu, Kaijie ; Xie, Daxing ; Zou, Yonglong ; Zhang, Tingting ; Pong, Rey Chen ; Xiao, Guanghua ; Fazli, Ladan ; Gleave, Martin ; He, Dalin ; Boothman, David A. ; Hsieh, Jer Tsong. / The mechanism of DAB2IP in chemoresistance of prostate cancer cells. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 17. pp. 4740-4749.
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abstract = "Purpose: 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. Experimental Design: 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 D2enhanced 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.",
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AU - Xie, Daxing

AU - Zou, Yonglong

AU - Zhang, Tingting

AU - Pong, Rey Chen

AU - Xiao, Guanghua

AU - Fazli, Ladan

AU - Gleave, Martin

AU - He, Dalin

AU - Boothman, David A.

AU - Hsieh, Jer Tsong

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