p53/E2F7 axis promotes temozolomide chemoresistance in glioblastoma multiforme

• Published in: BMC cancer Vol. 24; no. 1; pp. 317 - 13
• Main Authors: Meng, Jiao, Qian, Wei, Yang, Zhenkun, Gong, Lingli, Xu, Daxing, Huang, Hongbo, Jiang, Xinyi, Pu, Zhening, Yin, Ying, Zou, Jian
• Format: Journal Article
• Language: English
• Published: London BioMed Central 07.03.2024; BioMed Central Ltd; BMC
• Subjects: Analysis; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; Cancer Research; Care and treatment; Cell cycle; Cell growth; Cell Line, Tumor; Cell viability; Chemoresistance; Chemotherapy; Cyclin-dependent kinases; Cytotoxicity; Data analysis; Diagnosis; DNA damage; Dosage and administration; Doxorubicin; Drug resistance; Drug Resistance, Neoplasm - genetics; E2F7; E2F7 Transcription Factor - metabolism; Flow cytometry; Genes; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma multiforme; Glioma; Health aspects; Health Promotion and Disease Prevention; Humans; Kinases; Medical prognosis; Medicine/Public Health; Oncology; p53; p53 Protein; Prevention; Prognosis; Software; Surgical Oncology; Temozolomide; Temozolomide - pharmacology; Temozolomide - therapeutic use; Transcription factors; Transplantation; Tumor Suppressor Protein p53 - genetics; Tumors; China; United States > US; Temozolomide; Glioblastoma multiforme; E2F7; Chemoresistance; p53
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-024-12017-y

Background Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer, and chemoresistance poses a significant challenge to the survival and prognosis of GBM. Although numerous regulatory mechanisms that contribute to chemoresistance have been identified, many questions remain unanswered. This study aims to identify the mechanism of temozolomide (TMZ) resistance in GBM. Methods Bioinformatics and antibody-based protein detection were used to examine the expression of E2F7 in gliomas and its correlation with prognosis. Additionally, IC 50 , cell viability, colony formation, apoptosis, doxorubicin (Dox) uptake, and intracranial transplantation were used to confirm the role of E2F7 in TMZ resistance, using our established TMZ-resistance (TMZ-R) model. Western blot and ChIP experiments provided confirmation of p53-driven regulation of E2F7. Results Elevated levels of E2F7 were detected in GBM tissue and were correlated with a poor prognosis for patients. E2F7 was found to be upregulated in TMZ-R tumors, and its high levels were linked to increased chemotherapy resistance by limiting drug uptake and decreasing DNA damage. The expression of E2F7 was also found to be regulated by the activation of p53. Conclusions The high expression of E2F7, regulated by activated p53, confers chemoresistance to GBM cells by inhibiting drug uptake and DNA damage. These findings highlight the significant connection between sustained p53 activation and GBM chemoresistance, offering the potential for new strategies to overcome this resistance.