TRAIL and Noxa Are Selectively Upregulated in Prostate Cancer Cells Downstream of the RIG-I/MAVS Signaling Pathway by Nonreplicating Sendai Virus Particles

Abstract

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.

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

“…So far, only dsRNA cytosolic receptors have been implicated in the apoptotic effect induced by transfected poly(I:C) or viral dsRNA in prostate, gastric, breast, and melanoma cancers (20,(43)(44)(45). The most specific cytosolic receptor for poly(I:C) was demonstrated to be MDA5 (46), which mainly mediates antitumor effects (45).…”

“…In this regard, to confirm the canonical role of IRF3 in IFN type I induction, we transfected PC3 cells with a plasmid containing luciferase under the IFN-␤ promoter and assayed the luciferase activity after poly(I:C) alone and in combination with the IRF3 inhibitor BX795 for 3 h. DU145 cells were not tested because they have been described as not being able to produce IFN type I after poly(I:C) treatment (20). The pretreatment with BX795 abrogates the induction of IFN-␤ transcription, demonstrating the key role of IRF3 in the activation of the IFN-␤ promoter …”

“…We previously demonstrated that poly(I:C) (specific ligand of TLR3) induces apoptosis in the androgen-dependent prostate cancer cell line LNCaP in a TLR3-dependent fashion, whereas it has been observed to have a weaker apoptotic effect in the more aggressive and androgenindependent prostate cancer cell lines PC3 (18) and DU145 (19). Recently, Matsushima-Miyagi et al (20) demonstrated that non-replicating Sendai intracellular virus particles induce cancer-selective apoptosis via the up-regulation of TRAIL and Noxa downstream of the RIG-I/MAVS pathway in prostate cancer cell lines. In this regard, we have recently demonstrated that the encapsulation of poly(I:C) with three different formulations of cationic liposomes was up to 10 times more efficient than the free drug in eliminating both PC3 and DU145 metastatic prostate cancer cells (21).…”

Accumulation of Cytosolic Calcium Induces Necroptotic Cell Death in Human Neuroblastoma

“…Furthermore, we reported that HVJ-E stimulates an antitumor immune response by activating cytotoxic T lymphocytes and natural killer cells and suppressing regulatory T cells (25,26). Among these direct and indirect HVJ-E antitumor activities, we recently discovered that HVJ-E induces apoptosis via activation of the retinoic acid-inducible gene-I (RIG-I)/mitochondrial antiviral-signaling protein pathway followed by activation of interferon regulatory transcription factor (IRF)3 or IRF7 in prostate cancer cells (27). HVJ is a mouse parainfluenza virus that belongs to the paramixoviridae genus.…”

Highly Selective Photodynamic Therapy with a Short Drug-Light Interval Using a Cytotoxic Photosensitizer Porphyrus Envelope for Drug-Resistant Prostate Cancer Cells

“…As shown in Table 1, T/N ratio of cell death in PDT was higher than that of PE uptake. It is known that selective apoptosis in PC-3 cells but not in PNT2 cells is induced via recognition of fragmented HVJ-E's RNA genome by intracellular retinoic acid-inducible gene-I whose signaling pathway selectively activates apoptosis-inducing ligands in PC-3 cells [26]. In this study, survival rates of PC-3 cells were lower than those of , respectively.…”