Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype
Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype
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DOI：
10.1038/sj.onc.1207683
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发表时间：
2004-06-24
期刊：
影响因子：
8
通讯作者：
Testa, JR
中科院分区：
文献类型：
--
作者：
Apostolou, S;Klein, JO;Testa, JR
恶性间皮瘤 (MM) 是源自肺、心包和腹膜内层间皮细胞的侵袭性肿瘤，通常与职业石棉接触有关。抑制消减杂交用于鉴定 MM 细胞与正常间皮细胞相比差异表达的基因。使用这种方法分离出编码 15-kDa 含硒蛋白的基因 SEP15，随后显示该基因在 60% 的 MM 细胞系和肿瘤样本中被下调。 SEP15 多态性变体 1125A 位于 3'-UTR 中的 SECIS 识别元件中，可能会影响翻译过程中 Sec 掺入蛋白质的效率。由于先前的研究表明微量元素硒在动物模型和几种类型的人类癌症中作为化学预防剂的潜在作用，因此我们研究了硒对 MM 细胞的影响及其对 SEP15 基因型的依赖性。硒在 MM 细胞中以剂量依赖性方式抑制细胞生长并诱导细胞凋亡，但对正常间皮细胞的影响很小。然而，与表达野生型蛋白的MM细胞相比，下调SEP15或1125A变体的MM细胞对硒的生长抑制和凋亡作用的反应稍差。基于 RNAi 的敲低研究表明，SEP15 抑制使敏感的 MM 细胞对硒更具抵抗力。这些数据表明，对于因接触石棉而患多发性骨髓瘤的高风险个体，硒可能可用作化学预防剂，尽管具有 1125A 多态性的个体可能对膳食补硒的保护作用反应较弱。
Malignant mesotheliomas (MMs) are aggressive tumors derived from mesothelial cells lining the lungs, pericardium and peritoneum, and are often associated with occupational asbestos exposure. Suppression subtractive hybridization was used to identify genes differentially expressed in MM cells compared to normal mesothelial cells. A gene, SEP15, encoding a 15-kDa selenium-containing protein was isolated using this approach and was subsequently shown to be downregulated in similar to60% of MM cell lines and tumor specimens. A SEP15 polymorphic variant, 1125A, resides in the SECIS recognition element in the 3'-UTR and may influence the efficiency of Sec incorporation into the protein during translation. Since previous studies have implicated a potential role of the trace element selenium as a chemopreventive agent in animal models and in several types of human cancer, we investigated the effect of selenium on MM cells and its dependence on SEP15 genotype. Selenium was shown to inhibit cell growth and induce apoptosis in a dose-dependent manner in MM cells but had minimal effect on normal mesothelial cells. However, MM cells with downregulated SEP15 or the 1125A variant were somewhat less responsive to the growth inhibitory and apoptotic effects of selenium than MM cells expressing wild-type protein. RNAi-based knockdown studies demonstrated that SEP15 inhibition makes sensitive MM cells more resistant to selenium. These data imply that selenium may be useful as a chemopreventive agent in individuals at high risk of MM due to asbestos exposure, although those with the 1125A polymorphism may be less responsive to the protective benefits of dietary selenium supplementation.