1. ¹Department of Dermatology, University of Wisconsin, Madison, WI, USA
2. ²Medical Faculty, Institute of Human Genetics and Anthropology, University of Jena, Jena, Germany
3. ³Department of Biosciences, University of Kuopio, Kuopio, Finland

Correspondence: Dr H Mukhtar, Department of Dermatology, University of Wisconsin, 1300 University Avenue, Medical Science Center, 25B, Madison, WI 53706, USA. E-mail: hmukhtar@wisc.edu; Dr A Baniahmad, Medical Faculty, Institute of Human Genetics and Anthropology, University of Jena, Jena 07743, Germany. E-mail: aban@mti.uni-jena.de

⁴These authors contributed equally to this work.

Received 3 October 2007; Revised 29 November 2007; Accepted 3 December 2007; Published online 28 January 2008.

Abstract

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.