Journal
ONCOGENE
Volume 27, Issue 25, Pages 3596-3604Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1211016
Keywords
androgen receptor; casodex; invasion; prostate cancer; PP2; Src kinase
Funding
- NCI NIH HHS [R01CA120451, R01CA101039, R01CA78809, R01 CA101039, R01 CA078809, R01 CA120451] Funding Source: Medline
- NIDDK NIH HHS [P50 DK065303, P50DK065303-01] Funding Source: Medline
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Prostate cancer is one of the most prominent malignancies of elderly men in many Western countries including Europe and the United States with increasing trend worldwide. The growth of normal prostate as well as of prostate carcinoma cells depends on functional androgen receptor (AR) signaling. AR manifests the biological actions of androgens and its transcriptional activity is known to be influenced by signal transduction pathways. Here we show that Src, a nonreceptor tyrosine kinase, is overexpressed in androgen-independent prostate carcinoma C4-2 cells. Interestingly, the expression of Src was found to progressively increase (up to threefold) in transgenic adenocarcinoma of mouse prostate mice as a function of age and cancer progression. Blocking Src kinase function by a specific inhibitor, PP2, resulted in decreased AR transactivation function on two different reporters, mouse mammary tumor virus (MMTV) and prostate-specific antigen (PSA). Consistent with this, overexpression of a functional Src mutant also led to a dramatic decrease in AR transactivation potential in a hormone-dependent manner. Interference with Src function in C4-2 cells led to decreased recruitment of AR on the target gene PSA enhancer and also resulted in the abrogation of hormone-dependent PSA transcript induction. Src inhibition also led to a dramatic decrease in the cell invasion in addition to decreasing the cellular growth. We suggest that targeting Src kinase could be an effective strategy to inhibit prostate cancer growth and metastasis.
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