Oncolytic HSV-Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition.
| Publication Type | Academic Article |
| Authors | Otani Y, Yoo J, Chao S, Liu J, Jaime-Ramirez A, Lee T, Hurwitz B, Yan Y, Dai H, Glorioso J, Caligiuri M, Yu J, Kaur B |
| Journal | Clin Cancer Res |
| Volume | 26 |
| Issue | 10 |
| Pagination | 2381-2392 |
| Date Published | 03/05/2020 |
| ISSN | 1557-3265 |
| Keywords | Amyloid Precursor Protein Secretases, Brain Neoplasms, Glioblastoma, Herpesvirus 1, Human, Oncolytic Virotherapy, Receptors, Notch |
| Abstract | PURPOSE: To examine the effect of oncolytic herpes simplex virus (oHSV) on NOTCH signaling in central nervous system tumors. EXPERIMENTAL DESIGN: Bioluminescence imaging, reverse phase protein array proteomics, fluorescence microscopy, reporter assays, and molecular biology approaches were used to evaluate NOTCH signaling. Orthotopic glioma-mouse models were utilized to evaluate effects in vivo. RESULTS: We have identified that herpes simplex virus-1 (HSV-1; oncolytic and wild-type)-infected glioma cells induce NOTCH signaling, from inside of infected cells into adjacent tumor cells (inside out signaling). This was canonical NOTCH signaling, which resulted in activation of RBPJ-dependent transcriptional activity that could be rescued with dnMAML. High-throughput screening of HSV-1-encoded cDNA and miRNA libraries further uncovered that HSV-1 miR-H16 induced NOTCH signaling. We further identified that factor inhibiting HIF-1 (FIH-1) is a direct target of miR-H16, and that FIH-1 downregulation by virus encoded miR-H16 induces NOTCH activity. FIH-1 binding to Mib1 has been reported, but this is the first report that shows FIH-1 sequester Mib1 to suppress NOTCH activation. We observed that FIH-1 degradation induced NOTCH ligand ubiquitination and NOTCH activity. REMBRANDT and The Cancer Genome Atlas data analysis also uncovered a significant negative regulation between FIH-1 and NOTCH. Furthermore, combination of oHSV with NOTCH-blocking gamma secretase inhibitor (GSI) had a therapeutic advantage in two different intracranial glioma models treated with oncolytic HSV, without affecting safety profile of the virus in vivo. CONCLUSIONS: To our knowledge this is the first report to identify impact of HSV-1 on NOTCH signaling and highlights the significance of combining oHSV and GSI for glioblastoma therapy. |
| DOI | 10.1158/1078-0432.CCR-19-3420 |
| PubMed ID | 32139403 |
| PubMed Central ID | PMC7325527 |