Unidad de Investigación, Hospital Universitario Virgen de las Nieves, Granada, Spain.
PLoS One. 2011;6(8):e23887. doi: 10.1371/journal.pone.0023887. Epub 2011 Aug 24.
The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR) as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNα treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner, inducing phosphorylation of the protein synthesis translation initiation factor eIF-2α and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNα combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug.
化疗药物 5-FU 被广泛用于治疗多种癌症，但对该药物的耐药性仍然是一个主要的临床问题。由于凋亡介质的缺陷可能导致化疗耐药性，因此鉴定参与 5-FU 诱导凋亡的新靶点具有主要的临床意义。我们已经确定 ds-RNA 依赖性蛋白激酶（PKR）是 5-FU 诱导人结肠和乳腺癌细胞系凋亡的关键分子靶标。在几种具有不同 p53 状态的结肠和乳腺癌细胞系中，分析了在 5-FU 和 5-FU/IFNα治疗过程中 PKR 的分布和激活、细胞凋亡诱导和细胞毒性作用。PKR 蛋白在 p53 非依赖性方式被 5-FU 处理激活，诱导蛋白合成翻译起始因子 eIF-2α 的磷酸化，并通过细胞凋亡导致细胞死亡。此外，PKR 干扰促进了对 5-FU 治疗的反应降低，并且这些细胞不受 5-FU/IFNα联合的协同抗肿瘤活性的影响。这些结果表明，PKR 是 5-FU 的关键分子靶标，在该药物的临床应用中具有潜在的相关性。
