Targeting aurora kinases for the treatment of prostate cancer
Targeting aurora kinases for the treatment of prostate cancer
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DOI：
10.1158/0008-5472.can-05-2796
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Greenberg, Norman M.
中科院分区：
文献类型：
--
作者：
Lee, Edmund Chun Yu;Frolov, Anna;Greenberg, Norman M.
不适当的极光激酶表达可导致有丝分裂异常、中心体异常和染色体不稳定，从而导致异倍体和细胞转化。在这里，我们报告了Aurora-A和Aurora-B在人和小鼠前列腺癌以及前列腺癌细胞系中的高表达。在临床标本中，Aurora-A和Aurora-B在前列腺上皮内瘤变病变和前列腺癌中的水平显著高于非肿瘤标本。有趣的是，Aurora-A在非肿瘤性前列腺癌中的表达与精囊侵犯有关(Rho=0.275，P=0.0169)，在手术切缘阳性的前列腺癌中表达与精囊侵犯有关(Rho=0.265，P=0.0161)。Aurora-B在前列腺上皮内瘤变中的核表达与肿瘤的临床分期相关(Rho=-0.40，P=0.0474)，胞浆表达与精囊侵犯有关(Rho=0.282，P=0.0098)。来自TRAMP模型的细胞系和原发肿瘤也表达高水平的Aurora-A和Aurora-B。当人PC3、LNCaP和小鼠CIA细胞被有效的极光激酶抑制剂VX680处理时，癌细胞的存活率降低。当VX680与化疗药物阿霉素联合使用时，VX680会使细胞存活率进一步降低2倍。我们的发现支持极光激酶表达和前列腺癌之间的功能关系，以及小分子抑制剂在治疗方式中的应用。
Inappropriate expression of the Aurora kinases can induce aberrant mitosis, centrosome irregularities, and chromosomal instability, which lead to anueploidy and cell transformation. Here, we report that Aurora-A and Aurora-B are highly expressed in primary human and mouse prostate cancers and prostate cancer cell lines. In clinical samples, levels of Aurora-A and Aurora-B were significantly elevated in prostatic intraepithelial neoplasia lesions and prostate tumors when compared with the non-neoplastic samples. Interestingly, expression of Aurora-A in non-neoplastic prostates correlated with seminal vesicle invasion (rho = 0.275, P = 0.0169) and in prostate tumor with positive surgical margins (rho = 0.265, P = 0.0161). In addition, nuclear expression of Aurora-B in prostatic intraepithelial neoplasia lesions correlated with clinical staging of the tumor (rho = -0.4, P = 0.0474) whereas cytoplasmic expression in tumors correlated with seminal vesicle invasion (rho = 0.282, P = 0.0098). Cell lines and primary tumors derived from the TRAMP model were also found to express high levels of Aurora-A and Aurora-B. When human PC3, LNCaP, and mouse CIA cells were treated with the potent Aurora kinase inhibitor VX680, which attenuates phosphorylation of histone H3, cancer cell survival was reduced. VX680 could further reduce cell viability > 2-fold when used in combination with the chemotherapy drug doxorubicin. Our findings support a functional relationship between Aurora kinase expression and prostate cancer and the application of small-molecule inhibitors in therapeutic modalities.