AMOTL2­knockdown promotes the proliferation, migration and invasion of glioma by regulating ß­catenin nuclear localization.

Glioblastoma multiforme (GBM) is the most prevalent type of malignant cancer in the adult central nervous system; however, its mechanism remains unclear. Angiomotin­like 2 (AMOTL2) is a member of the motin family of angiostatin­binding proteins. It has been reported as an oncogene in cervical and breast cancer, but its association with glioma remains unknown. The aim of the present study was to investigate AMOTL2­regulated processes in glioma cell lines using extensive in vitro assays and certain bioinformatics tools. These results revealed that AMOTL2 was downregulated in high­grade glioma cells and tissues, with patients with glioma exhibiting a high AMOTL2 expression having a higher survival rate. The results of the glioma cell phenotype experiment showed that AMOTL2 suppressed GBM proliferation, migration and invasion. In addition, immunoblotting, co­immunoprecipitation and immunofluorescence assays demonstrated that AMOTL2 could directly bind to ß­catenin protein, the key molecule of the Wnt signaling pathway, and regulate its downstream genes by regulating ß­catenin nuclear translocation. In conclusion, the present study demonstrated that AMOTL2 inhibited glioma proliferation, migration and invasion by regulating ß­catenin nuclear localization. Thus, AMOTL2 may serve as a therapeutic target to further improve the prognosis and prolong survival time of patients with glioma.

Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway.

Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of p-AMPK and amlexanox led to the reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that compared to other groups treated with each component alone, TMZ combined with amlexanox effectively reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly.

We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brain tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin.