Efficient eradication of hormone-resistant human prostate cancers by inactivated Sendai virus particle.
Hormone-refractory prostate cancer is one of the intractable human cancers in the world. Here, we examined the direct tumor-killing activity of inactivated Sendai virus particle [hemagglutinating virus of Japan envelope (HVJ-E)] through induction of Type I interferon (IFN) in the hormone-resistant human prostate cancer cell lines PC3 and DU145. Preferential binding of HVJ-E to PC3 and DU145 over hormone-sensitive prostate cancer cell and normal prostate epithelium was observed, resulting in a number of fused cells. After HVJ-E treatment, a number of IFN-related genes were up-regulated, resulting in Type I IFN production in PC3 cells. Then, retinoic acid-inducible gene-I (RIG-I) helicase which activates Type I IFN expression after Sendai virus infection was up-regulated in cancer cells after HVJ-E treatment. Produced IFN-alpha and -beta enhanced caspase 8 expression via Janus kinases/Signal Transducers and Activators of Transcription pathway, activated caspase 3 and induced apoptosis in cancer cells. When HVJ-E was directly injected into a mass of PC3 tumor cells in SCID (severe combined immunodeficiency) mice, a marked reduction in the bulk of each tumor mass was observed and 85% of the mice became tumor-free. Although co-injection of an anti-asialo GM1 antibody with HVJ-E into each tumor mass slightly attenuated the tumor suppressive activity of HVJ-E, significant suppression of tumor growth was observed even in the presence of anti-asialo GM1 antibody. This suggests that natural killer cell activation made small contribution to tumor regression following HVJ-E treatment in hormone-resistant prostate cancer model in vivo. Thus, HVJ-E effectively targets hormone-resistant prostate cancer by inducing apoptosis in tumor cells, as well as activating anti-tumor immunity.
Kawaguchi
Yoshifumi
Y
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
Miyamoto
Yasuhide
Y
Inoue
Takehiro
T
Kaneda
Yasufumi
Y
D000818:Animals; D017209:Apoptosis; D019496:Cancer Vaccines / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007372:Interferons / Q000502:physiology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D050791:STAT Transcription Factors / Q000502:physiology; D029082:Sendai virus / Q000276:immunology*; D014771:Virion
D019496:Cancer Vaccines; D050791:STAT Transcription Factors; D007372:Interferons; D020169:Caspases; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases