Myc Confers Androgen-Independent Prostate Cancer Cell Growth

J Clin Invest. 2003 Dec;112(11):1724-31. doi: 10.1172/JCI19035.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / physiology*
  • Cell Cycle Proteins*
  • Cell Division
  • Cell Line, Tumor
  • Cyclin A / analysis
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Humans
  • Male
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-myc / physiology*
  • Signal Transduction
  • Transcription Factors / analysis
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Androgen Antagonists
  • Androgens
  • Cell Cycle Proteins
  • Cyclin A
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Tumor Suppressor Protein p53