Bernard David, Pourtier-Manzanedo Albin, Gil Jesús, Beach David H
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kindom.
J Clin Invest. 2003 Dec;112(11):1724-31. doi: 10.1172/JCI19035.
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.
前列腺癌是西方国家诊断率和死亡率最高的癌症之一。一个主要的临床问题是在抗激素治疗期间发生雄激素非依赖性前列腺癌（AIPC）。这些肿瘤从雄激素依赖性转变为非依赖性的分子机制尚不清楚，这对开发新疗法构成了挑战。基于显示AIPC中c-myc基因扩增的基因数据，我们研究了c-myc赋予AIPC细胞生长的能力。过表达c-myc的人雄激素依赖性前列腺癌细胞在无雄激素的情况下独立生长，并在雄激素缺乏的条件下呈现致瘤特性。通过雄激素受体（AR）的药理学抑制剂或针对AR或c-myc的RNA干扰对信号通路进行分析表明，c-myc通过多种生长效应器作用于AR的下游。因此，c-myc是雄激素依赖性生长所必需的，异位表达后可诱导雄激素非依赖性生长。此外，针对c-myc的RNA干扰表明，人AIPC细胞（无论AR阳性或阴性）的生长都需要c-myc表达。此外，我们还表明，过表达c-myc的细胞保留了功能性p53通路，因此对依托泊苷有反应。
