An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

Abstract

Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retain their resistance to all VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…Interestingly, we showed that VSV-directed TP53 transgene expression dramatically inhibited type I IFN responses in cancer cells and that it occurred through p53-mediated inhibition of the NF-kB pathway. Importantly, VSV-encoded p53 did not inhibit antiviral signalling in normal human pancreatic ductal cells [98].…”

“…Previously, enhanced oncotoxicity was observed for VSV-M(mut)-mp53, which encodes mouse WT p53 in addition to the mutated M protein [97]. Our own group recently engineered novel VSV recombinants encoding human WT p53 or a chimeric p53-CC, which can evade the dominant-negative activities of endogenously expressed mutant p53 [98]. Interestingly, we showed that VSV-directed TP53 transgene expression dramatically inhibited type I IFN responses in cancer cells and that it occurred through p53-mediated inhibition of the NF-kB pathway.…”

Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus

“…As many cancers have defective type I interferon antiviral signaling, VSV-ΔM51 can still replicate in and kill cancer cells (32,33). In addition, to facilitate the visualization of viral infection, VSV recombinants used in this study encode either the near-infrared red fluorescent protein (RFP) (34) or green fluorescent protein (GFP) (31) open reading frame (ORF) inserted between the VSV G and L genes.…”

Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

“…Surprisingly, and in contrast with the expected enhancement of antiviral signaling by p53, expression of genes associated with type I IFN signaling pathway was dramatically attenuated in p53 transgene-expressing cells. For example, although a 291-fold increase in IFN-β transcripts was detected in cells infected with the VSV recombinant that does not express p53, only a 25-fold increase in IFN-β transcripts was observed in cells infected with VSV-p53wt 67 . These data suggest that OV-encoded p53 can simultaneously produce anti-cancer activities while assisting, rather than inhibiting, virus replication in cancer cells.…”

“…Indeed, such activities of virus-encoded p53 transgenes in cancer cells could reduce OV efficacy by decreasing virus oncoselectivity. To address this important concern, our recent study engineered and compared VSV recombinants either expressing WT human p53 fused to near-infrared fluorescent protein (eqFP650, herein called RFP) (“VSV-p53wt”) or expressing RFP only (“VSV”) for the abilities of these viruses to induce type I IFN signaling in several human pancreatic ductal adenocarcinoma (PDAC) cell lines 67 . Surprisingly, and in contrast with the expected enhancement of antiviral signaling by p53, expression of genes associated with type I IFN signaling pathway was dramatically attenuated in p53 transgene-expressing cells.…”