Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota.
Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota.
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DOI：
10.1158/0008-5472.can-08-1449
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Guo W;Wu S;Liu J;Fang B
K-Ras突变经常在各种癌症中发现，并与治疗抵抗或预后不良有关。类似地，最近在具有蛋白激酶C1（PKC 1）过表达的癌症患者中观察到不良结果，PKC 1是一种非典型蛋白激酶C，其被致癌Ras蛋白激活并且是体内K-Ras诱导的转化和结肠癌发生所需的。到目前为止，还没有有效的药物用于治疗K-Ras突变或PKC i过表达的癌症。通过合成致死性筛选，我们确定了一种小化合物（命名为oncrasin-1），其在低或亚微摩尔浓度下有效地杀死具有K-Ras突变的各种人肺癌细胞。细胞毒性作用与凋亡诱导相关，如通过在oncrasin-1处理敏感细胞后凋亡细胞的增加和caspase-3和caspase-8的活化所证明的。用oncrasin-1处理还导致敏感细胞的细胞核中的PKCι异常聚集，但在抗性细胞中不。此外，oncrasin-1诱导的细胞凋亡被K-Ras或PKC 1的siRNA阻断，表明oncrasin-1靶向新的K-Ras/PKC 1途径。体内施用oncrasin-1抑制K-ras突变体人肺肿瘤异种移植物的生长>70%，并延长携带这些肿瘤的裸鼠的存活，而不引起可检测的毒性。我们的研究结果表明，oncrasin-1或其活性类似物可能是一类新的抗癌药物，有效地杀死K-Ras突变癌细胞。
K-Ras mutations are frequently found in various cancers, and are associated with resistance to treatment or poor prognosis. Similarly, poor outcomes have recently been observed in cancer patients with overexpression of protein kinase C iota (PKCι), an atypical protein kinase C that is activated by oncogenic Ras protein and is required for K-Ras-induced transformation and colonic carcinogenesis in vivo. Thus far, there is no effective agent for treatment of cancers with K-Ras mutations or PKCι overexpression. By synthetic lethality screening, we identified a small compound (designated oncrasin-1) that effectively kills various human lung cancer cells with K-Ras mutations at low or submicromolar concentrations. The cytotoxic effects correlated with apoptosis induction as was evidenced by increase of apoptotic cells and activation of caspase-3 and caspase-8 upon the treatment of oncrasin-1 in sensitive cells. Treatment with oncrasin-1 also led to abnormal aggregation of PKCι in nucleus of sensitive cells but not in resistant cells. Furthermore, oncrasin-1 induced apoptosis was blocked by siRNA of K-Ras or PKCι suggesting that oncrasin-1 is targeted to a novel K-Ras/PKCι pathway. The in vivo administration of oncrasin-1 suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity. Our results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents which effectively kill K-Ras mutant cancer cells.