CSIG-15. INNOVATIVE COMPUTATIONAL PLATFORM ADDRESSES PROSTAGLANDIN E RECEPTOR 3 AS THE MASTER REGULATOR MEDIATING RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS
| Autor: | Tarun E. Hutchinson, Son Le, Dongjiang Chen, David Tran |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Prostaglandin E receptor 3
Cancer Research Temozolomide Computer science Cell Signaling and Signaling Pathways Master regulator medicine.disease medicine.disease_cause Nuclear translocation Oncology Prostaglandin E Receptor Cancer research medicine Neurology (clinical) Carcinogenesis Homing-associated cell adhesion molecule Glioblastoma medicine.drug |
| Zdroj: | Neuro Oncol |
| Popis: | OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. The addition of TTFields resulted in a significant improvement in overall survival. However, most GBM patients eventually develop resistance to TTFields and the mechanism remains unexplored. METHODS Multiple GBM cell lines were treated continuously at clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay, stemness markers such as CD44 and increased tumorigenesis when implanted into mouse brain. Using an innovative computational platform-NETZEN, we methodically dissected this stemness program in resistant cells. 3 networks were found disrupted and all play critical roles in GBM stemness. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked regulator responsible for resistance. PTGER3 is rapidly upregulated both in vitro and in vivo upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Immunofluorescence staining shows PTGER3’s nuclear translocation along with Lamin A/C disruption in response to TTFields. Pharmacological inhibition of PTGER3 using aspirin or PTGER3-specific inhibitors resensitized or prevent cells becoming resistance to TTFields. CONCLUSIONS We have identified a novel regulator PTGER3 at the apex that plays a critical role in TTFields resistance. This is a potential therapeutic target to reduce resistance to TTFields therapy in GBM. |
| Databáze: | OpenAIRE |
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