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.

Pi Chu Liu,Xian Wei Su,Xiang Hu,Yi Deng,Tat Ming Chan,Wai Sang Poon,Jing Ye Zhou,Gang Lu,Cheng Dong Wang,Javier S Castresana

doi:10.1371/journal.pone.0171157

Abstract

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.

Highlights

Cancer is a class of diseases characterized by abnormal cell proliferation and survival, which are closely associated with dysregulated programmed cell death or apoptosis[1]
Lovastatin statistically up-regulates death receptor 5 (DR5) expression dose-dependently in all four cell lines, in A172 and U87 cell lines (Fig 1D). These findings indicated that lovastatin treatment promotes DR5 expression in multiple human glioblastoma cell lines, which provides a molecular basis by which lovastatin sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioblastoma multiforme (GBM)
We further investigated the molecular basis underlying the effects of lovastatin in the sensitization of TRAIL-mediated apoptosis in the glioblastoma cells, and tested pre-clinically the efficacy of combined treatment of lovastatin and TRAIL on subcutaneous brain tumors in mice

Summary

Introduction

Cancer is a class of diseases characterized by abnormal cell proliferation and survival, which are closely associated with dysregulated programmed cell death or apoptosis[1]. One of the pathways that trigger the initiation of apoptosis is mediated through death receptors (DR) on the cell surface. Eight death receptors have been characterized so far, including TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAILR1/DR4) and TRAILR2/DR5[2, 3]. The binding of natural death ligands (TNF cytokines) to DR4 or DR5 triggers the formation of death-inducing signaling complex (DISC)[4], which involves oligomerization of the DR and recruitment of Fas-associated death domain protein (FADD), proapoptotic caspase 8–10 as well as antiapoptotic cellular FADD-like IL-1βconverting enzyme-inhibitory protein (cFLIP), via homotypic protein-protein interactions between their death domains. Decoy receptors (DcRs) that lack functional death domains interact with death ligands, but do not trigger the formation of signaling complexes[3]

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Conclusion