ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma
Autor: | Rohit Sachdeva, Sunit Das, Kimia Ghannad-Zadeh, David G. Munoz, Jennifer Guan, Michael D. Taylor, Sayf Al-Omaishi, Oleksandra Kaskun, Jiefei Tong, Peter B. Dirks, Sandra Smiljanic, Michael F. Moran, Megan Wu, Keren Isaev, Jüri Reimand, Jeffrey Chan, A. Sorana Morrissy, Angela Celebre, Taylor M. Wilson |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Inhibitor of Differentiation Protein 1 Cancer Research medicine.medical_treatment Brain tumor Breast Neoplasms medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Glioma Antineoplastic Combined Chemotherapy Protocols medicine Temozolomide Animals Humans Phosphorylation Antineoplastic Agents Alkylating Melanoma Chemotherapy business.industry Brain Neoplasms Pimozide Cancer medicine.disease Xenograft Model Antitumor Assays 3. Good health ErbB Receptors Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Tumor progression Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female business Carcinogenesis Glioblastoma medicine.drug |
Zdroj: | Cancer research. 79(16) |
ISSN: | 1538-7445 |
Popis: | Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. Significance: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival. |
Databáze: | OpenAIRE |
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