Myc confers androgen-independent prostate cancer cell growth.
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.
Bernard
David
D
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kindom.
Pourtier-Manzanedo
Albin
A
Gil
Jesús
J
Beach
David H
DH
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000502:physiology*; D018797:Cell Cycle Proteins; D002455:Cell Division; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000032:analysis; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000726:Androgen Antagonists; D000728:Androgens; D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53