Loss of Raf kinase inhibitory protein induces radioresistance in prostate cancer.
Loss of Raf kinase inhibitory protein induces radioresistance in prostate cancer.
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DOI：
10.1016/j.ijrobp.2008.04.072
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发表时间：
2008-09-01
影响因子：
7
通讯作者：
Keller, Evan T.
中科院分区：
文献类型：
--
作者：
Woods, Kathleen M.;Grewal, Navdeep K.;Markwart, Sonja M.;Vellaichamy, Adaikkalam;Chinnaiyan, Arul M.;Yeung, Kam;Ray, Michael E.;Keller, Evan T.
外照射放射治疗通常用于试图治愈局限性前列腺癌（PCa），但仅对播散性疾病具有姑息性。Raf激酶抑制蛋白（RKIP）是一种转移抑制因子，其表达在约50%的局部PCa组织中减少，并且在转移灶中不存在。化疗药物已显示通过诱导RKIP表达来诱导肿瘤细胞凋亡。我们的目标是测试放射治疗是否通过诱导RKIP表达类似地诱导细胞凋亡。将C4-2B PCa细胞系工程化以过表达或低表达RKIP。在细胞培养中测试工程化细胞的凋亡，并在放射治疗后在小鼠中测试肿瘤消退。辐射诱导PCa细胞RKIP表达和凋亡。RKIP的过度表达使PCa细胞对辐射诱导的凋亡敏感;然而，靶向RKIP的短发夹，使得辐射不能诱导RKIP表达，保护细胞免受辐射诱导的凋亡。在小鼠模型中，PCa细胞中RKIP的敲低减少了辐射诱导的细胞凋亡。操纵RKIP表达后改变的基因的分子概念图显示，与辐射改变的基因的概念呈负相关。本文提供的数据表明，如在原发性PCa肿瘤和转移瘤中所见，RKIP的丢失赋予了对辐射诱导的细胞凋亡的保护。因此，可以想象，RKIP的损失赋予PCa细胞在远处位点的生长优势，因为RKIP的损失将减少细胞凋亡，有利于增殖。
External beam radiation therapy is often used as in an attempt to cure localized prostate cancer (PCa), but is only palliative against disseminated disease. Raf Kinase Inhibitory Protein (RKIP) is a metastasis suppressor whose expression is reduced in approximately 50% of localized PCa tissues and is absent in metastases. Chemotherapeutic agents have been shown to induce tumor apoptosis through induction of RKIP expression. Our goal was to test if radiation therapy similarly induces apoptosis through induction of RKIP expression. The C4-2B PCa cell line was engineered to over express or under express RKIP. The engineered cells were tested for apoptosis in cell culture and tumor regression in mice following radiation treatment. Radiation induced both RKIP expression and apoptosis of PCa cells. Over expression of RKIP sensitized PCa cells to radiation-induced apoptosis; whereas, short-hairpin targeting of RKIP, so that radiation could not induce RKIP expression, protected cells from radiation-induced apoptosis. In a murine model, knockdown of RKIP in PCa cells diminished radiation-induced apoptosis. Molecular concept mapping of genes altered upon manipulation of RKIP expression revealed that an inverse correlation with the concept of genes altered by irradiation. The data presented here indicate that the loss of RKIP, as seen in primary PCa tumors and metastases, confers protection against radiation-induced apoptosis. Therefore, it is conceivable that loss of RKIP confers a growth advantage upon PCa cells at distant sites since loss of RKIP would decrease apoptosis, favoring proliferation.
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