TRAIL and Noxa Are Selectively Upregulated in Prostate Cancer Cells Downstream of the RIG-I/MAVS Signaling Pathway by Nonreplicating Sendai Virus Particles
TRAIL and Noxa Are Selectively Upregulated in Prostate Cancer Cells Downstream of the RIG-I/MAVS Signaling Pathway by Nonreplicating Sendai Virus Particles
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DOI：
10.1158/1078-0432.ccr-12-1595
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发表时间：
2012-11-15
影响因子：
11.5
通讯作者：
Kaneda, Yasufumi
中科院分区：
文献类型：
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作者：
Matsushima-Miyagi, Taeko;Hatano, Koji;Kaneda, Yasufumi
目的：溶瘤病毒治疗癌症主要取决于癌细胞中病毒的选择性复制。然而，日本无复制血凝病毒（HVJ；仙台病毒）包膜（HVJ-E）与有复制能力的活 HVJ 一样有效地抑制人类癌细胞的生长，且不会对非恶性细胞产生毒性作用。在这里，我们分析了 HVJ-E 溶瘤活性的分子机制。 实验设计：在前列腺癌细胞系中阐明了负责 HVJ-E 诱导癌细胞死亡的分子，并在非肥胖糖尿病-严重联合免疫缺陷 (NOD-SCID) 小鼠中评估了 HVJ-E 对原位前列腺癌的作用。 结果：脂质体介导的 HVJ-E 病毒 RNA 基因组片段的转移抑制了前列腺癌细胞的活力，但不是非癌性前列腺上皮的活力。使用 siRNA 的敲低实验表明，HVJ-E 诱导的癌细胞选择性杀伤是由视黄酸诱导基因 I (RIG-I) 和线粒体抗病毒信号蛋白 (MAVS) 介导的。在 RIG-I/MAVS 通路下游，在去势抵抗性前列腺癌细胞系 PC3 中，TNF 相关凋亡诱导配体 (TRAIL) 和 Noxa 均被 HVJ-E 上调，但在非癌性前列腺上皮细胞系 PNT2 中则不然。 TRAIL siRNA（而非 Noxa siRNA）显着抑制 HVJ-E 诱导的 PC3 细胞死亡。然而，Noxa siRNA 有效抑制了 HVJ-E 诱导的另一种去势抵抗性前列腺癌细胞系 DU145 细胞中的细胞死亡，其中 HVJ-E 上调了 Noxa 而不是 TRAIL。此外，在注射 HVJ-E 的免疫缺陷小鼠中，原位前列腺癌被显着根除。 结论：RIG-I/MAVS 信号通路代表了癌症治疗的一个有吸引力的靶点。临床癌症研究； 18（22）； 6271-83。 (C)2012 AACR。
Purpose: The treatment of cancer with oncolytic viruses primarily depends on the selective viral replication in cancer cells. However, a replication-incompetent hemagglutinating virus of Japan (HVJ; Sendai virus) envelope (HVJ-E) suppresses the growth of human cancer cells as effectively as replication-competent live HVJ without producing toxic effects in nonmalignant cells. Here, we analyze the molecular mechanism of the oncolytic activity of HVJ-E.Experimental Design: The molecules responsible for HVJ-E-induced cancer cell death were elucidated in prostate cancer cell lines, and the effect of HVJ-E on orthotopic prostate cancers was evaluated in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice.Results: The liposome-mediated transfer of viral RNA genome fragments from HVJ-E suppressed the viability of prostate cancer cells but not the viability of the noncancerous prostate epithelium. Knockdown experiments using siRNAs showed that the cancer cell-selective killing induced by HVJ-E was mediated by retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). Downstream of the RIG-I/MAVS pathway, both TNF-related apoptosis-inducing ligand (TRAIL) and Noxa were upregulated by HVJ-E in the castration-resistant prostate cancer cell line PC3 but not in the noncancerous prostate epithelial cell line PNT2. TRAIL siRNA but not Noxa siRNA significantly inhibited HVJ-E-induced cell death in PC3 cells. However, Noxa siRNA effectively suppressed HVJ-E-induced cell death in DU145 cells, another castration-resistant prostate cancer cell line, in which Noxa but not TRAIL was upregulated by HVJ-E. Furthermore, the orthotopic prostate cancers were dramatically eradicated in immunodeficient mice injected with HVJ-E.Conclusion: The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy. Clin Cancer Res; 18(22); 6271-83. (C)2012 AACR.