STAT3 activation promotes oncolytic HSV1 replication in glioma cells.
Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy.
Dardinger Center for Neuro-Oncology and Neurosciences, Department of Neurological Surgery, James Cancer Hospital/Solove Research Institute, the Ohio State University, Columbus, Ohio, United States of America.
Kazuo
K
Okemoto
Benjamin
B
Wagner
Hans
H
Meisen
Amy
A
Haseley
Balveen
B
Kaur
Ennio Antonio
EA
Chiocca
D000927:Anticonvulsants / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy / Q000821:virology*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005910:Glioma / Q000378:metabolism / Q000628:therapy / Q000821:virology*; D006561:Herpes Simplex / Q000235:genetics / Q000628:therapy / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D050130:Oncolytic Virotherapy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology; D014779:Virus Replication
D000927:Anticonvulsants; D007370:Interferon Type I; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014635:Valproic Acid; D008156:Luciferases