Myc confers androgen-independent prostate cancer cell growth
David Bernard, … , Jesús Gil, David H. Beach
David Bernard, … , Jesús Gil, David H. Beach
Published December 1, 2003
Citation Information: J Clin Invest. 2003;112(11):1724-1731. https://doi.org/10.1172/JCI19035.
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Article Oncology

Myc confers androgen-independent prostate cancer cell growth

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.

Authors

David Bernard, Albin Pourtier-Manzanedo, Jesús Gil, David H. Beach

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Figure 1

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c-myc expression renders LNCaP cells androgen-independent. LNCaP cells w...
c-myc expression renders LNCaP cells androgen-independent. LNCaP cells were infected with GFP or c-myc retroviral vectors and selected with hygromycin. One day after seeding, bicalutamide treatment was started and renewed every 2 days. (a) Growth curve assays. Cells were seeded in triplicate in 24-well plates. At 4-day intervals, the cell number was analyzed. The black lines represent untreated cells, and the gray lines show bicalutamide-treated cells. (b) Colony-formation assays. Cells (200,000) were seeded onto plates, and after 15 days of treatment with bicalutamide, the cells were stained using crystal violet. (c) DNA content analysis. After 11 days of bicalutamide treatment, cells were fixed, stained using propidium iodide, and analyzed. (d) Cell division analysis. After infection and selection, the cells were stained with CFDA SE dye and seeded in the presence of bicalutamide. Flow cytometry analysis on 10,000 cells was performed at day 9 and the number of cell divisions is presented. (e) Soft agar assays. Cells were plated in soft agar media containing or not containing androgen. Analysis of the appearance of the foci was performed after 2 weeks.