RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3.
RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3.
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RK-33放射敏感性通过阻断RNA解旋酶DDX3来使前列腺癌细胞敏感。
DOI：
10.1158/0008-5472.can-16-0440
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Raman V
中科院分区：
文献类型：
--
作者：
Xie M;Vesuna F;Tantravedi S;Bol GM;Heerma van Voss MR;Nugent K;Malek R;Gabrielson K;van Diest PJ;Tran PT;Raman V
尽管在诊断和治疗方面取得了进展，但前列腺癌是男性中最常见的癌症，也是癌症相关死亡率的第二高原因。我们鉴定了一种RNA解旋酶基因DDX 3（DDX 3X），它在前列腺癌中过表达，其表达与高Gleason评分直接相关。DDX 3在侵袭性前列腺癌细胞系DU 145和22 Rv 1中的敲低导致克隆形成显著降低。为了靶向DDX 3，我们合理地设计了一种小分子RK-33，它停靠在DDX 3的ATP结合结构域中。功能研究表明，RK-33优先结合DDX 3，干扰其活性。RK-33处理前列腺癌细胞系DU 145、22 Rv 1和LNCaP（其具有高DDX 3水平）降低增殖并诱导G1期细胞周期停滞。相反，低DDX 3表达细胞系PC 3在RK-33处理后表现出很少的变化。重要的是，使用RK-33和放射的组合研究在体外和前列腺癌的异种移植模型中均表现出协同效应，证明了RK-33作为放射增敏剂的作用。总之，这些结果表明，通过RK-33阻断DDX 3与放射治疗的组合是治疗局部晚期前列腺癌的可行选择。
Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second highest cause of cancer-related mortality. We identified an RNA helicase gene, DDX3 (DDX3X), which is overexpressed in prostate cancers, and whose expression is directly correlated with high Gleason scores. Knockdown of DDX3 in the aggressive prostate cancer cell lines DU145 and 22Rv1 resulted in significantly reduced clonogenicity. To target DDX3, we rationally designed a small molecule, RK-33, which docks into the ATP-binding domain of DDX3. Functional studies indicated that RK-33 preferentially bound to DDX3 and perturbed its activity. RK-33 treatment of prostate cancer cell lines DU145, 22Rv1, and LNCaP (which have high DDX3 levels) decreased proliferation and induced a G1 phase cell-cycle arrest. Conversely, the low DDX3–expressing cell line, PC3, exhibited few changes following RK-33 treatment. Importantly, combination studies using RK-33 and radiation exhibited synergistic effects both in vitro and in a xenograft model of prostate cancer demonstrating the role of RK-33 as a radiosensitizer. Taken together, these results indicate that blocking DDX3 by RK-33 in combination with radiation treatment is a viable option for treating locally advanced prostate cancer.