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.
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.
Zhoul
Jian
J
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA.
Hernandez
Gina
G
Tu
Szu-Wei
SW
Huang
Chien-Ling
CL
Tseng
Ching-Ping
CP
Hsieh
Jer-Tsong
JT
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059002:Androgen Receptor Antagonists; D051017:Apoptosis Regulatory Proteins; D001667:Binding, Competitive; D000081247:CSK Tyrosine-Protein Kinase; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008297:Male; D010770:Phosphotransferases / Q000378:metabolism*; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D059002:Androgen Receptor Antagonists; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; D013196:Dihydrotestosterone; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human