IKBKE enhances TMZ-chemoresistance through upregulation of MGMT expression in glioblastoma.

Abstract

PURPOSE:

Glioblastoma multiforme (GBM) is the most common and aggressive malignant type of brain tumor. Despite advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. Multidrug resistance and high recurrence are two of the major challenges in successfully treating brain tumors. IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) is a major oncogenic protein in tumors and can inhibit glioblastoma cell proliferation, migration, and tumorigenesis. Our study aimed to investigate the mechanism of IKBKE enhancing the resistance of glioma cells to temozolomide.

METHODS:

For the in vitro experiments, LN18 and U118 glioblastoma cells were treated with a combination of sh/oe-IKBKE lentivirus and TMZ. Cell proliferation was determined by the EdU assay and colony formation assays. Apoptosis was analyzed by the TUNEL assay. In vivo, LN18 NC and LN18 sh-IKBKE cells were implanted into the cerebrums of nude mice to detect the effect of combination therapy. The protein and mRNA levels were assayed by western blot, immunohistochemistry, and qRT-PCR.

RESULTS:

In this study, we demonstrated that IKBKE enhances the resistance of glioblastoma cells to temozolomide (TMZ) by activating the AKT/NF-κB signaling pathway to upregulate the expression of the DNA repair enzyme o6-methylguanine-dna methyltransferase (MGMT). In glioblastoma cells, IKBKE knockdown enhances apoptosis and suppresses cell proliferation, clone formation, and tumor development in vivo induced by TMZ. However, overexpression of IKBKE reduces the effects of TMZ.

CONCLUSION:

Our studies suggest that inhibition of IKBKE can enhance the therapeutic effect of TMZ on GBM in vitro and in vivo, providing new research directions and therapeutic targets for the treatment of GBM.

• Authors: G Guo, Y Sun, R Hong, J Xiong, Y Lu, Y Liu, J Lu, Z Zhang, C Guo, Y Nan, Q Huang
• Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (Clin Transl Oncol) Vol. 22 Issue 8 Pg. 1252-1262 (Aug 2020) ISSN: 1699-3055 [Electronic] Italy
• PMID: 31865606 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• NF-kappa B
• Neoplasm Proteins
• RNA, Messenger
• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• Proto-Oncogene Proteins c-akt
• I-kappa B Kinase
• IKBKE protein, human
• DNA Repair Enzymes
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Apoptosis (physiology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• DNA Modification Methylases (metabolism)
• DNA Repair Enzymes (metabolism)
• Drug Resistance, Multiple (physiology)
• Drug Resistance, Neoplasm (physiology)
• Female
• Gene Knockdown Techniques
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• I-kappa B Kinase (antagonists & inhibitors, genetics, metabolism, pharmacology)
• Lentivirus
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (metabolism)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism, pharmacology)
• Neoplasm Transplantation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (analysis)
• Temozolomide (pharmacology)
• Transduction, Genetic (methods)
• Tumor Suppressor Proteins (metabolism)
• Up-Regulation
• Xenograft Model Antitumor Assays