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Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells

Oncogene volume 27, pages 3596–3604 (2008)Cite this article

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.

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Acknowledgements

We thank Dr GP Reddy for gift of Casodex, Dr GN Thalmann for providing C4-2 cells and Dr Sarah Courtneidge for mammalian expression vectors of wt and mutant Src. This work was supported by US PHS Grants RO1CA78809; RO1CA101039, RO1CA120451 and O'Brian center Grant P50DK065303-01 to HM and Association of International Cancer research (AICR, UK) and DFG-BA1457/3 grant to AB.

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  1. M Asim and I A Siddiqui: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, University of Wisconsin, Madison, WI, USA

    M Asim, I A Siddiqui, B B Hafeez & H Mukhtar

  2. Medical Faculty, Institute of Human Genetics and Anthropology, University of Jena, Jena, Germany

    M Asim & A Baniahmad

  3. Department of Biosciences, University of Kuopio, Kuopio, Finland

    A Baniahmad

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  1. M Asim
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  2. I A Siddiqui
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  3. B B Hafeez
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  4. A Baniahmad
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  5. H Mukhtar
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Correspondence to A Baniahmad or H Mukhtar.

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Asim, M., Siddiqui, I., Hafeez, B. et al. Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells. Oncogene 27, 3596–3604 (2008). https://doi.org/10.1038/sj.onc.1211016

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