J Clin Invest 112(11): 1724-1731

Myc confers androgen-independent prostate cancer cell growth

^{Wolfson Institute for Biomedical Research, University College London, London, United Kingdom}^{Sciences Naturelles 3, Université des Sciences et Techniques de Lille, Villeneuve D’Ascq, France}

Address correspondence to: David H. Beach, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kindom. Phone: 0032-2555-6016; Fax: 0032-2555-6257; E-mail: moc.tenretnitb@hcaebhd.

Received 2003 May 27; Accepted 2003 Sep 30.

Abstract

Prostate cancer is one of the most diagnosed and mortal cancers in western countries. A major clinical problem is the development of androgen-independent prostate cancer (AIPC) during antihormonal treatment. The molecular mechanisms underlying the change from androgen dependence to independence of these tumors are poorly understood and represent a challenge to develop new therapies. Based on genetic data showing amplification of the c-myc gene in AIPC, we studied the ability of c-myc to confer AIPC cell growth. Human androgen-dependent prostate cancer cells overexpressing c-myc grew independently of androgens and presented tumorigenic properties in androgen-depleted conditions. Analysis of signalling pathways by pharmacological inhibitors of the androgen receptor (AR) or by RNA interference directed against AR or c-myc showed that c-myc acted downstream of AR through multiple growth effectors. Thus c-myc is required for androgen-dependent growth and following ectopic expression can induce androgen-independent growth. Moreover, RNA interference directed against c-myc showed that growth of human AIPC cells, AR-positive or -negative, required c-myc expression. Furthermore, we showed that c-myc–overexpressing cells retain a functional p53 pathway and thus respond to etoposide.

Abstract

Acknowledgments

We thank P. Kerai, A. Carnero, D. Monte, and R. Kypta for helpful suggestions and discussion of the manuscript, L. Martinez for technical assistance, and M. Pagano for the LZRS/Skp2 retroviral vector. This investigation was supported by a grant from Cancer Research UK. Jesús Gil is a recipient of long-term fellowships from the European Molecular Biology Organization (EMBO) and the Human Frontier Science Program.

Acknowledgments

Footnotes

David Bernard’s present address is: Free University of Brussels Laboratory of Molecular Virology Faculty of Medicine, Brussels, Belgium.

Conflict of interest: The authors have declared that no conflict of interest exists.

Nonstandard abbreviations used: dihydrotestosterone (DHT); androgen-independent prostate cancer (AIPC); androgen receptor (AR); p53 dominant negative (p53DN); pRetroSuper (pRS); prostrate specific antigen (PSA); prostrate specific membrane antigen (PSMA).

Footnotes

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