Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines.
Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines.
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DOI：
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发表时间：
2000-12
期刊：
影响因子：
11.2
通讯作者：
E. Bernhard;E. Stanbridge;Swati Gupta;Anjali K. Gupta;Daniel Soto;V. Bakanauskas;G. Cerniglia;R. Muschel;W. Mckenna
中科院分区：
文献类型：
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作者：
E. Bernhard;E. Stanbridge;Swati Gupta;Anjali K. Gupta;Daniel Soto;V. Bakanauskas;G. Cerniglia;R. Muschel;W. Mckenna
ras癌基因的转化导致许多但不是所有细胞的辐射存活率增加。此外，异戊烯基转移酶抑制剂通过阻断翻译后修饰来抑制ras蛋白，从而使具有致癌ras的细胞放射增敏。这些结果表明，致癌ras有助于内在的辐射抗性。然而，因为ras癌基因的引入并不能增加所有细胞的辐射存活率，并且因为异戊烯基转移酶抑制剂靶向ras以外的分子，所以这些研究留下了ras增加肿瘤细胞内在辐射抗性的结论。在这里，我们表明，在人类肿瘤细胞（DLD-1和HT 1080，分别）的K-或N-ras癌基因的基因失活导致放射敏感性增加。将激活的N-ras基因重新导入HT 1080系，失去了其突变等位基因，导致辐射抗性增加。这项研究进一步支持了这一假设，即激活的ras的表达可以有助于人类肿瘤细胞的内在辐射抗性，并将这一发现扩展到ras家族的K-和N-成员。这些发现支持了在癌症治疗中靶向ras失活的策略的发展。
Transformation with ras oncogenes results in increased radiation sur vival in many but not all cells. In addition, prenyltransferase inhibitors which inhibit ras proteins by blocking posttranslational modification radiosensitize cells with oncogenic ras. These findings suggest that oncogenic ras contributes to intrinsic radiation resistance. However, because introduction of ras oncogenes does not increase radiation survival in all cells and because prenyltransferase inhibitors target molecules other than ras, these studies left the conclusion that ras increases the intrinsic radi ation resistance of tumor cells in doubt. Here we show that genetic inactivation of K- or N-ras oncogenes in human tumor cells (DLD-1 and HT1080, respectively) leads to increased radiosensitivity. Reintroduction of the activated N-ras gene into the HT1080 line, having lost its mutant allele, resulted in increased radiation resistance. This study lends further support to the hypothesis that expression of activated ras can contribute to intrinsic radiation resistance in human tumor cells and extends this finding to the K- and N- members of the ras family. These findings support the development of strategies that target ras for inactivation in the treatment of cancer.