HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2′,5′-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand
HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2′,5′-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand
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DOI：
10.1158/0008-5472.can-04-2226
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Silverman, RH
中科院分区：
文献类型：
--
作者：
Malathi, K;Paranjape, JM;Silverman, RH
遗传性前列腺癌1（HPC 1）等位基因映射到RNASEL基因，该基因编码一种与干扰素的抗病毒活性有关的蛋白质（RNase L）。为了研究RNase L在前列腺癌细胞凋亡中的可能作用，我们通过稳定表达小干扰RNA（siRNA），将DU 145人前列腺癌细胞系中RNase L的水平降低了数倍。对照细胞表达与RNase L序列具有三个错配核苷酸的siRNA。RNA酶L缺陷的细胞，而不是对照细胞，对RNA酶L激活剂2 '，5'-寡腺苷酸（2-5A）引起的细胞凋亡具有高度抗性。令人惊讶的是，RNase L缺陷细胞也对拓扑异构酶（Topo）I抑制剂（喜树碱、拓扑替康或SN-38）和肿瘤坏死因子相关凋亡诱导配体[TRAIL（Apo 2L）]的联合治疗的凋亡具有高度抗性。相比之下，表达RNA酶L抑制剂RLI（HP 68）的siRNA的细胞显示响应于单独的Topo I抑制剂或与TRAIL组合的增强的凋亡。c-Jun NH 2-末端激酶的抑制剂减少了由2-5A或喜树碱和TRAIL的组合处理诱导的细胞凋亡，从而暗示c-Jun NH 2-末端激酶参与细胞凋亡信号通路。此外，前列腺癌细胞对来自2-5A与TRAIL或Topo I抑制剂的组合的凋亡敏感，而正常前列腺上皮细胞对凋亡部分抵抗。这些发现表明RNase L整合并放大了在用2-5A、Topo I抑制剂和TRAIL治疗前列腺癌细胞期间产生的凋亡信号。
The hereditary prostate cancer 1 (HPC1) allele maps to the RNASEL gene encoding a protein (RNase L) implicated in the antiviral activity of interferons. To investigate the possible role of RNase L in apoptosis of prostate cancer cells, we decreased levels of RNase L by severalfold in the DU145 human prostate cancer cell line through the stable expression of a small interfering RNA (siRNA). Control cells expressed siRNA with three mismatched nucleotides to the RNase L sequence. Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A). Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)]. In contrast, cells expressing siRNA to the RNase L inhibitor RLI (HP68) showed enhanced apoptosis in response to Topo I inhibitor alone or in combination with TRAIL. An inhibitor of c-Jun NH2-terminal kinases reduced apoptosis induced by treatment with either 2-5A or the combination of camptothecin and TRAIL, thus implicating c-Jun NH2-terminal kinase in the apoptotic signaling pathway. Furthermore, prostate cancer cells were sensitive to apoptosis from the combination of 2-5A with either TRAIL or Topo I inhibitor, whereas normal prostate epithelial cells were partially resistant to apoptosis. These findings indicate that RNase L integrates and amplifies apoptotic signals generated during treatment of prostate cancer cells with 2-5A, Topo I inhibitors, and TRAIL.