Division of Gene Therapy Science, Departments of Urology and Pediatric Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Clin Cancer Res. 2012 Nov 15;18(22):6271-83. doi: 10.1158/1078-0432.CCR-12-1595. Epub 2012 Sep 26.
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.
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.
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.
The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy.
溶瘤病毒治疗癌症主要依赖于病毒在癌细胞中的选择性复制。然而，无复制能力的血凝性日本病毒（HVJ；仙台病毒）包膜（HVJ-E）在不产生非恶性细胞毒性作用的情况下，与复制能力强的活 HVJ 一样有效地抑制人类癌细胞的生长。在此，我们分析了 HVJ-E 溶瘤活性的分子机制。
在前列腺癌细胞系中阐明了导致 HVJ-E 诱导的癌细胞死亡的分子，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。
脂质体介导的 HVJ-E 病毒 RNA 基因组片段转移抑制了前列腺癌细胞的活力，但不影响非癌前列腺上皮的活力。siRNA 敲低实验表明，HVJ-E 诱导的癌细胞选择性杀伤是由维甲酸诱导基因 I（RIG-I）和线粒体抗病毒信号蛋白（MAVS）介导的。在去势抵抗性前列腺癌细胞系 PC3 中，RIG-I/MAVS 通路下游的 TRAIL 和 Noxa 均由 HVJ-E 上调，但在非癌前列腺上皮细胞系 PNT2 中则没有。TRAIL siRNA 而非 Noxa siRNA 显著抑制了 PC3 细胞中 HVJ-E 诱导的细胞死亡。然而，在另一个去势抵抗性前列腺癌细胞系 DU145 中，Noxa siRNA 有效地抑制了 HVJ-E 诱导的细胞死亡，而 HVJ-E 上调了 Noxa 而非 TRAIL。此外，在注射 HVJ-E 的免疫缺陷小鼠中，原位前列腺癌被显著根除。
RIG-I/MAVS 信号通路是癌症治疗的一个有吸引力的靶点。
