Vorinostat and Bortezomib Synergistically Cause Ubiquitinated Protein Accumulation in Prostate Cancer Cells
Vorinostat and Bortezomib Synergistically Cause Ubiquitinated Protein Accumulation in Prostate Cancer Cells
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DOI：
10.1016/j.juro.2012.07.108
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发表时间：
2012-12-01
影响因子：
6.6
通讯作者：
Asano, Tomohiko
中科院分区：
文献类型：
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作者：
Sato, Akinori;Asano, Takako;Asano, Tomohiko
目的：蛋白质遍在化是一种用于治疗恶性肿瘤的新策略。我们研究了组蛋白脱乙酰酶抑制剂伏立诺他（Cayman Chemical，安阿伯，Michigan）和蛋白酶体抑制剂硼替佐米（LC Laboratories，Woburn，马萨诸塞州）是否会协同引起前列腺癌细胞中泛素化蛋白的积累。评估细胞活力和细胞凋亡诱导。使用PC-3细胞在鼠皮下肿瘤模型中评价体内功效。使用RNA干扰检测雄激素受体表达对硼替佐米疗效的影响。泛素化蛋白、细胞周期相关蛋白和乙酰化组蛋白表达的变化进行了评估。结果：雄激素受体表达似乎降低硼替佐米活性。PC-3和DU 145细胞比LNCaP细胞对硼替佐米更敏感，并且LNCaP细胞中雄激素受体表达的沉默增强硼替佐米活性。伏立诺他和硼替佐米在鼠异种移植模型中协同诱导细胞凋亡，抑制前列腺癌细胞生长并抑制肿瘤生长。联合用药降低了细胞周期蛋白D1和细胞周期蛋白依赖性激酶4的表达，并增加了p21的表达。该组合协同引起泛素化蛋白和组蛋白乙酰化的积累。这种组蛋白乙酰化是泛素化蛋白积累的结果。结论：伏立诺他和硼替佐米通过引起泛素化蛋白在细胞中积累协同抑制前列腺癌细胞的生长。目前的研究提供了一个框架，用于测试晚期前列腺癌患者的组合。
Purpose: Protein ubiquitination is a novel strategy used to treat malignancies. We investigated whether the histone deacetylase inhibitor vorinostat (Cayman Chemical, Ann Arbor, Michigan) and the proteasome inhibitor bortezomib (LC Laboratories, Woburn, Massachusetts) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells.Materials and Methods: LNCaP, PC-3 and DU 145 cells (ATCC (TM)) were treated with vorinostat and/or bortezomib. Cell viability and induction of apoptosis were assessed. In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC-3 cells. The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference. Changes in the expression of ubiquitinated proteins, cell cycle associated proteins and acetylated histone were evaluated.Results: Androgen receptor expression seemed to decrease bortezomib activity. PC-3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity. Vorinostat and bortezomib synergistically induced apoptosis, inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model. The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression, and increased p21 expression. The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation. This histone acetylation was a consequence of the accumulation of ubiquitinated proteins.Conclusions: Vorinostat and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells. The current study provides a framework for testing the combination in patients with advanced prostate cancer.