The role of DOC-2/DAB2 in modulating androgen receptor-mediated cell growth via the nongenomic c-Src-mediated pathway in normal prostatic epithelium and cancer

Jian Zhoul, Gina Hernandez, Szu Wei Tu, Chien Ling Huang, Ching Ping Tseng, Jer Tsong Hsieh

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Prostate cancer is initially responsive to androgen ablation, but prostate cancer tumors invariably progress to an androgen-independent state that is ultimately lethal. The onset of the androgen-independent prostate cancer is often associated with up-regulation of the androgen receptor that can cause antagonists to exhibit agonistic activity, which could lead to the failure of androgen ablation therapy. We describe a unique protein-DOC-2/DAB2 (differentially expressed in ovarian cancer-2/disabled 2)-that antagonizes androgen receptor-mediated cell growth in prostate cancer cells via interaction with c-Src protein. This interaction causes inactivation of Erk and Akt proteins critical for proliferation and survival of prostate cancer cells. However, DOC-2/DAB2 does not change the capacity of androgen receptor to regulate the transcription of androgen-responsive reporter genes, indicating that DOC-2/DAB2 selectively inhibits androgen receptor-mediated cell growth in androgen-independent prostate cancer by disrupting the androgen receptor/c-Src complex. In normal prostatic epithelia, DOC-2/DAB2 protein levels are more abundant than androgen receptor protein levels and reduced endogenous DOC-2/DAB2 protein levels in these cells by DOC-2/DAB2 RNA interference result in enhancing androgen receptor-mediated cell growth. We conclude that DOC-2/DAB2 can modulate androgen receptor-mediated cell growth in both normal and malignant prostatic epithelial cells and the outcome of this study could evolve into a new therapeutic strategy of prostate cancer.

Original languageEnglish (US)
Pages (from-to)9906-9913
Number of pages8
JournalCancer research
Volume65
Issue number21
DOIs
StatePublished - Nov 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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