Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) Combination Therapy

• Published in: PloS one Vol. 12; no. 1; p. e0171157
• Main Authors: Liu, Pi Chu, Lu, Gang, Deng, Yi, Wang, Cheng Dong, Su, Xian Wei, Zhou, Jing Ye, Chan, Tat Ming, Hu, Xiang, Poon, Wai Sang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2017; Public Library of Science (PLoS)
• Subjects: Animals; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Biology and Life Sciences; Biotechnology; Brain; Brain cancer; Brain tumors; Breast cancer; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Coinjection; Combination therapy; Combined treatment; Deactivation; Disease Models, Animal; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - enzymology; Glioblastoma - pathology; Glioblastoma cells; HEK293 Cells; Humans; In vivo methods and tests; Inactivation; Injection; JNK protein; Kinases; Ligands; Lovastatin; Lovastatin - administration & dosage; Lovastatin - pharmacology; Lovastatin - therapeutic use; MAP kinase; MAP Kinase Signaling System - drug effects; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Necrosis; Neurosurgery; NF-kappa B - metabolism; NF-κB protein; Proteins; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Research and Analysis Methods; Rodents; Signaling; Subcutaneous Tissue - drug effects; Subcutaneous Tissue - pathology; Surgery; Therapy; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TNF-Related Apoptosis-Inducing Ligand - therapeutic use; TRAIL protein; Tumor necrosis factor; Tumor necrosis factor-TNF; Up-Regulation - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171157

Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5) in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.