Kammler Susanne, Lykke-Andersen Søren, Jensen Torben Heick
Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology, University of Aarhus, CF Møllers Alle, Building 1130, 8000 Aarhus C., Denmark.
Mol Cancer Res. 2008 Jun;6(6):990-5. doi: 10.1158/1541-7786.MCR-07-2217.
The drug 5-fluorouracil (5-FU) is a widely used chemotherapeutic in the treatment of solid tumors. Recently, the essential 3'-5' exonucleolytic multisubunit RNA exosome was implicated as a target for 5-FU in yeast. Here, we show that this is also the case in human cells. HeLa cells depleted of the inessential exosome component hRrp6, also called PM/Scl100, are significantly growth impaired relative to control cells after 5-FU administration. The selective stabilization of bona fide hRrp6 RNA substrates on 5-FU treatment suggests that this exosome component is specifically targeted. Consistently, levels of hRrp6 substrates are increased in two 5-FU-sensitive cell lines. Interestingly, whereas down-regulation of all tested core exosome components results in decreased hRrp6 levels, depletion of hRrp6 leaves levels of other exosome components unchanged. Taken together, our data position hRrp6 as a promising target for antiproliferative intervention.
药物5-氟尿嘧啶（5-FU）是一种广泛用于治疗实体瘤的化疗药物。最近，重要的3'-5'核酸外切酶多亚基RNA外切体被认为是酵母中5-FU的作用靶点。在此，我们表明在人类细胞中也是如此。与对照细胞相比，在施用5-FU后，缺失非必需外切体组分hRrp6（也称为PM/Scl100）的HeLa细胞生长明显受损。5-FU处理后真正hRrp6 RNA底物选择性稳定，表明该外切体组分是特异性作用靶点。一致地，在两种对5-FU敏感的细胞系中，hRrp6底物水平升高。有趣的是，虽然所有测试的核心外切体组分的下调都会导致hRrp6水平降低，但hRrp6缺失时其他外切体组分的水平保持不变。综上所述，我们的数据表明hRrp6是抗增殖干预的一个有前景的靶点。
