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Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.
- Source :
-
Journal of cell science [J Cell Sci] 2019 Mar 14; Vol. 132 (5). Date of Electronic Publication: 2019 Mar 14. - Publication Year :
- 2019
-
Abstract
- 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.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2019. Published by The Company of Biologists Ltd.)
- Subjects :
- Animals
Cell Death
Cell Line, Tumor
Cricetinae
Herpes Simplex pathology
Humans
Immediate-Early Proteins genetics
Immunity, Innate genetics
Kidney pathology
Mutation genetics
Oncolytic Virotherapy
Promyelocytic Leukemia Protein genetics
Telomere Homeostasis
Ubiquitin-Protein Ligases genetics
Herpes Simplex metabolism
Herpesvirus 1, Human physiology
Immediate-Early Proteins metabolism
Kidney metabolism
Promyelocytic Leukemia Protein metabolism
Ubiquitin-Protein Ligases metabolism
X-linked Nuclear Protein deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9137
- Volume :
- 132
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of cell science
- Publication Type :
- Academic Journal
- Accession number :
- 30745338
- Full Text :
- https://doi.org/10.1242/jcs.222349