PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses.
The oncotropic phenotypes of several viruses correlate with tumor-associated deficiencies within interferon (IFN) signaling pathways. This observation formed the conceptual basis for developing oncolytic viruses deleted for viral proteins that inhibit the host IFN-dependent antiviral response, such as herpes simplex virus type-1 infected cell protein-0 (ICP0) and vesicular stomatitis virus matrix protein. Many viruses have evolved means to disrupt promyelocytic leukemia protein (PML) nuclear bodies. For example, ICP0 promotes PML degradation to inhibit the antiviral activities of this IFN-stimulated gene. As PML is downregulated in a variety of tumors, we hypothesized ICP0-null herpes simplex type-1 viruses are selectively oncolytic in tumors with impaired PML expression. We illustrate that ICP0-null herpes simplex type-1 viruses target tumor cells that either possess impaired PML signaling or cannot upregulate PML because of impaired IFN responsiveness. Disruption of PML signaling through overexpression of the dominant-negative protein PML-retinoic acid receptor alpha in PML-positive cells renders them sensitive to oncolysis by ICP0-null herpes simplex virus type-1 and vesicular stomatitis virus M protein mutant viruses, whereas PML overexpression reverses this phenomenon. Together, these data illustrate that PML mediates an antiviral mechanism that predicts the tropism of IFN-sensitive oncolytic viruses. To our knowledge, these viruses are the first examples of anti-cancer therapeutics capable of targeting deficiencies in PML expression.
Sobol
P T
PT
Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Hummel
J L
JL
Rodrigues
R M
RM
Mossman
K L
KL
D014408:Biomarkers, Tumor / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D018139:Simplexvirus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D056189:Viral Tropism
D014408:Biomarkers, Tumor; D017874:Immediate-Early Proteins; D016898:Interferon-alpha; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1