Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency
| Autor: | Eugene H. Y. Choi, Sonja Frölich, Roger D. Everett, Jane R. Noble, Ted Wong, Christine E. Napier, Roger R. Reddel, Anthony J. Cesare, Erdahl Teber, Mingqi Han |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Intrinsic immunity
X-linked Nuclear Protein Telomerase Oncolytic virus Ubiquitin-Protein Ligases viruses Herpesvirus 1 Human Synthetic lethality Promyelocytic Leukemia Protein Kidney Post-transcriptional control Immediate-Early Proteins 03 medical and health sciences Promyelocytic leukemia protein 0302 clinical medicine Cell Line Tumor Cricetinae medicine Animals Humans ATRX 030304 developmental biology Oncolytic Virotherapy Soft-tissue malignancies 0303 health sciences PML Cell Death biology Telomere Homeostasis Herpes Simplex Sarcoma Translational control Cell Biology medicine.disease Immunity Innate 3. Good health Leukemia Telomeres Mutation Cancer cell biology.protein Cancer research 030217 neurology & neurosurgery Research Article |
| Zdroj: | Journal of Cell Science |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.222349 |
| Popis: | Cancers that utilize the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of promyelocytic leukemia nuclear bodies (PML NBs) that are required for intrinsic immunity to various viruses. Here, we asked whether ATRX deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus. Summary: ATRX deficiency in cancer cells induces downregulation of PML, rendering the cells highly sensitive to lysis with ICP0-null mutant herpes simplex virus-1, with potential therapeutic applications. |
| Databáze: | OpenAIRE |
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