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 replicationcompetent 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.

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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.</p><p><b>Conclusion:</b> The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy. <i>Clin Cancer Res; 18(22); 6271–83. ©2012 AACR</i>.</p></div>

<p>PDF file - 395K, Figure S1. Selective apoptosis in DU145 cells induced by HVJ-E. Figure S2. The effect of poly (I:C) on cell survival. Figure S3. No significant changes in the expression of Bax, Puma, Bcl-xL or Bcl-2 were observed in cells treated with HVJ-E. Figure S4. Selective expression of the death receptors for TRAIL in PC3 cells and the decoy receptors for TRAIL in PNT2 cells. Figure S5. Suppression of HVJ-E-induced cell death by IRF7 siRNA in PC3 cells and by IRF3 siRNA in DU145 cells. Figure S6. Histological analysis and TUNEL staining of subcutaneous tumors injected with HVJ-E.</p>

<p>PDF file - 395K, Figure S1. Selective apoptosis in DU145 cells induced by HVJ-E. Figure S2. The effect of poly (I:C) on cell survival. Figure S3. No significant changes in the expression of Bax, Puma, Bcl-xL or Bcl-2 were observed in cells treated with HVJ-E. Figure S4. Selective expression of the death receptors for TRAIL in PC3 cells and the decoy receptors for TRAIL in PNT2 cells. Figure S5. Suppression of HVJ-E-induced cell death by IRF7 siRNA in PC3 cells and by IRF3 siRNA in DU145 cells. Figure S6. Histological analysis and TUNEL staining of subcutaneous tumors injected with HVJ-E.</p>

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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.</p><p><b>Conclusion:</b> The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy. <i>Clin Cancer Res; 18(22); 6271–83. ©2012 AACR</i>.</p></div>