RRAD Promotes EGFR-Mediated STAT3 Activation and Induces Temozolomide Resistance of Malignant Glioblastoma
| Autor: | Do-Hyun Nam, Chaehwa Park, Seon-Yong Yeom |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
STAT3 Transcription Factor
Homeobox protein NANOG Cancer Research Endosomes Biology medicine.disease_cause Receptor tyrosine kinase SOX2 Cancer stem cell Cell Line Tumor Spheroids Cellular Temozolomide Tumor Cells Cultured medicine Humans STAT3 Antineoplastic Agents Alkylating Cell Nucleus Protein Stability Prognosis Dacarbazine ErbB Receptors Gene Expression Regulation Neoplastic Protein Transport Cell Transformation Neoplastic Oncology Drug Resistance Neoplasm ras Proteins Cancer research biology.protein Stem cell Glioblastoma Carcinogenesis medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 13:3049-3061 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Glioblastoma multiforme (GBM) is an extremely aggressive brain cancer with a median survival of less than 2 years. GBM is characterized by abnormal activation of receptor tyrosine kinase and constitutively activated STAT3. Although EGFR phosphorylation and STAT3 activation are essential for the maintenance of GBM cancer stem cells, the molecular mechanism underlying endosome-mediated STAT3 activation is not fully understood. In the current study, we showed that GTP-binding protein RRAD (RAS associated with diabetes, RAD) physically associates with EGFR, and EEA1, enhancing the stability and endosome-associated nuclear translocation of EGFR. Functionally, RRAD contributes to the activation of STAT3 and expression of the stem cell factors OCT4, NANOG, and SOX2, thereby enhancing self-renewing ability, tumor sphere formation, EMT, and in vivo tumorigenesis. Most importantly, RRAD contributes to poor survival in patients with GBM. RRAD expression is correlated with temozolomide resistance, and, conversely, depletion of RRAD leads to sensitization of highly temozolomide-resistant GBM cells. Our data collectively support a novel function of RRAD in STAT3 activation and provide evidence that RRAD acts as a positive regulator in the EGFR signaling pathway. These results demonstrate a critical role for RRAD in GBM tumorigenesis and provide a rationale for the development of pharmacologic inhibitors of RRAD in GBM. Mol Cancer Ther; 13(12); 3049–61. ©2014 AACR. |
| Databáze: | OpenAIRE |
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