Gao Hui, Ouyang Xuesong, Banach-Petrosky Whitney A, Gerald William L, Shen Michael M, Abate-Shen Cory
Center for Advanced Biotechnology and Medicine, Cancer Institute of New Jersey, and Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854, USA.
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14477-82. doi: 10.1073/pnas.0606836103. Epub 2006 Sep 14.
Androgen independence is responsible for most prostate cancer lethality, yet currently there are no effective clinical treatments. We have been investigating the mechanisms underlying androgen-independent prostate cancer in Nkx3.1;Pten mutant mice, which display salient features of the disease, including a requirement for wild-type androgen receptor (AR) signaling. We now demonstrate that the Akt and Erk MAP kinase signaling pathways are activated in androgen-independent lesions of these mice. Forced activation of either Akt or Erk signaling in an androgen-responsive prostate cancer cell line promotes hormone-independent but AR-dependent growth in culture. Although these pathways act additively in culture, they act synergistically in vivo to promote tumorigenicity and androgen independence in the context of the prostate microenvironment. We propose that androgen independence emerges by means of epithelial-stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma.
雄激素非依赖性是大多数前列腺癌致死的原因，但目前尚无有效的临床治疗方法。我们一直在研究Nkx3.1;Pten突变小鼠中雄激素非依赖性前列腺癌的潜在机制，这些小鼠表现出该疾病的显著特征，包括对野生型雄激素受体（AR）信号传导的需求。我们现在证明，Akt和Erk MAP激酶信号通路在这些小鼠的雄激素非依赖性病变中被激活。在雄激素反应性前列腺癌细胞系中强制激活Akt或Erk信号传导可促进培养物中激素非依赖性但AR依赖性的生长。尽管这些信号通路在培养中具有累加作用，但它们在体内协同作用，在前列腺微环境中促进肿瘤发生和雄激素非依赖性。我们提出，雄激素非依赖性是通过上皮-基质竞争出现的，其中Akt和Erk的激活促进前列腺上皮中的AR活性，同时抵消基质的拮抗作用。
