Zhang Hui, Wang Jian, Pang Bo, Liang Rui-xia, Li Suping, Huang Pei-tang, Wang Ruoxiang, Chung Leland W K, Zhau Haiyen E, Huang Cuifen, Zhou Jian-guang
Laboratory of Molecular Oncology, Institute of Biotechnology, Beijing, P. R. China.
Cancer Res. 2007 Sep 15;67(18):8906-13. doi: 10.1158/0008-5472.CAN-06-4214.
PC-1/PrLZ gene overexpression has been identified to be associated with prostate cancer progression. Previous studies have revealed that PC-1 possesses transforming activity and confers malignant phenotypes to mouse NIH3T3 cells. However, the functional relevance of PC-1 expression changes during prostate cancer development and progression remains to be evaluated. In this study, gain-of-function and loss-of-function analyses in LNCaP and C4-2 cells, respectively, were implemented. Experimental data showed that PC-1 expression was in positive correlation with prostate cancer cell growth and anchor-independent colony formation in vitro, as well as tumorigenicity in athymic BALB/c mice. Moreover, PC-1 expression was also found to promote androgen-independent progression and androgen antagonist Casodex resistance in prostate cancer cells. These results indicate that PC-1 contributes to androgen-independent progression and malignant phenotypes in prostate cancer cells. Furthermore, molecular evidence revealed that PC-1 expression stimulated Akt/protein kinase B signaling pathway, which has been implicated to play important roles in promoting androgen refractory progression in prostate cancer. Increased PC-1 levels in C4-2 cells may represent an adaptive response in prostate cancer, mediating androgen-independent growth and malignant progression. Inhibiting PC-1 expression may represent a novel therapeutic strategy to delay prostate cancer progression.
已证实PC-1/PrLZ基因过表达与前列腺癌进展相关。先前的研究表明，PC-1具有转化活性，并赋予小鼠NIH3T3细胞恶性表型。然而，PC-1表达变化在前列腺癌发生和进展过程中的功能相关性仍有待评估。在本研究中，分别在LNCaP和C4-2细胞中进行了功能获得和功能丧失分析。实验数据表明，PC-1表达与前列腺癌细胞体外生长、非锚定依赖的集落形成以及无胸腺BALB/c小鼠体内的致瘤性呈正相关。此外，还发现PC-1表达促进前列腺癌细胞的雄激素非依赖性进展和对雄激素拮抗剂比卡鲁胺的耐药性。这些结果表明，PC-1促成前列腺癌细胞的雄激素非依赖性进展和恶性表型。此外，分子证据显示，PC-1表达刺激了Akt/蛋白激酶B信号通路，该通路在促进前列腺癌雄激素难治性进展中发挥重要作用。C4-2细胞中PC-1水平升高可能代表前列腺癌中的一种适应性反应，介导雄激素非依赖性生长和恶性进展。抑制PC-1表达可能代表一种延缓前列腺癌进展的新治疗策略。
