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TROY signals through JAK1-STAT3 to promote glioblastoma cell migration and resistance
- Source :
- Neoplasia (New York, N.Y.), Neoplasia: An International Journal for Oncology Research, Vol 22, Iss 9, Pp 352-364 (2020)
- Publication Year :
- 2020
- Publisher :
- Neoplasia Press, 2020.
-
Abstract
- Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a discouraging prognosis. Its aggressive and highly infiltrative nature renders the current standard treatment of maximal surgical resection, radiation, and chemotherapy relatively ineffective. Identifying the signaling pathways that regulate GBM migration/invasion and resistance is required to develop more effective therapeutic regimens to treat GBM. Expression of TROY, an orphan receptor of the TNF receptor superfamily, increases with glial tumor grade, inversely correlates with patient overall survival, stimulates GBM cell invasion in vitro and in vivo, and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in a preclinical intracranial xenograft model. Here, we have identified for the first time that TROY interacts with JAK1. Increased TROY expression increases JAK1 phosphorylation. In addition, increased TROY expression promotes STAT3 phosphorylation and STAT3 transcriptional activity that is dependent upon JAK1. TROY-mediated activation of STAT3 is independent of its ability to stimulate activity of NF-κB. Inhibition of JAK1 activity by ruxolitinib or knockdown of JAK1 expression by siRNA significantly inhibits TROY-induced STAT3 activation, GBM cell migration, and decreases resistance to temozolomide. Taken together, our data indicate that the TROY signaling complex may represent a potential therapeutic target with the distinctive capacity to exert effects on multiple pathways mediating GBM cell invasion and resistance.
- Subjects :
- 0301 basic medicine
STAT3 Transcription Factor
Cancer Research
Original article
GBM, Glioblastoma
TROY
Antineoplastic Agents
Apoptosis
lcsh:RC254-282
Receptors, Tumor Necrosis Factor
STAT3
03 medical and health sciences
0302 clinical medicine
Biomarkers, Tumor
Tumor Cells, Cultured
Medicine
Gene silencing
Humans
Migration
Cell Proliferation
Orphan receptor
Gene knockdown
TNF, tumor necrosis factor
Temozolomide
biology
business.industry
Brain Neoplasms
Cell migration
Janus Kinase 1
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
TNFR, tumor necrosis factor receptor
STAT, signal transducer and activator of transcription
Gene Expression Regulation, Neoplastic
030104 developmental biology
JAK1
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
biology.protein
Phosphorylation
Signal transduction
business
JAK, Janus kinase
Glioblastoma
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14765586 and 15228002
- Volume :
- 22
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Neoplasia (New York, N.Y.)
- Accession number :
- edsair.doi.dedup.....a972f330b0569d41b78dc2c160322c91