McCall P, Gemmell L K, Mukherjee R, Bartlett J M S, Edwards J
Division of Cancer Sciences and Molecular Pathology, Glasgow Royal Infirmary, Glasgow, UK.
Br J Cancer. 2008 Mar 25;98(6):1094-101. doi: 10.1038/sj.bjc.6604152. Epub 2008 Mar 18.
Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (P=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (P=0.014), and an increase in expression of pAkt(473) and pAR(210) were associated with decreased disease-specific survival (P=0.0019 and 0.0015, respectively). Protein expression of pAkt(473) and pAR(210) also strongly correlated (P<0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target.
细胞系研究表明,PI3K/Akt信号通路在激素难治性前列腺癌(HRPC)中上调,并可导致雄激素受体(AR)磷酸化。因此,本研究旨在确定这是否与临床HRPC的发生有关。采用免疫组织化学方法研究了68例配对的激素敏感性和难治性前列腺癌肿瘤中Akt和AR的表达及磷酸化状态。在激素难治性组织中,只有磷酸化AR(pAR)与复发后死亡时间缩短相关(P = 0.003)。然而,当研究从激素敏感性前列腺癌向难治性前列腺癌转变过程中的表达增加时,PI3K表达增加与生化复发时间缩短相关(P = 0.014),pAkt(473)和pAR(210)表达增加与疾病特异性生存率降低相关(分别为P = 0.0019和0.0015)。在激素难治性前列腺肿瘤中,pAkt(473)和pAR(210)的蛋白表达也呈强相关(P < 0.001,c.c. = 0.711)。这些结果利用临床标本提供了证据,表明PI3K/Akt信号通路的上调与HRPC发生过程中AR的磷酸化相关,提示该通路可能是一个潜在的治疗靶点。