Amlexanox, a selective inhibitor of IKBKE, generates anti-tumoral effects by disrupting the Hippo pathway in human glioblastoma cell lines

Liu, Yang; Lü, Jie; Zhang, Zhimeng; Zhu, Lin; Dong, Shicai; Guo, Gaochao; Li, Ruohong; Yang, Nan; Yu, Kai; Zhong, Yue; Huang, Qiang

doi:10.1038/cddis.2017.396

Cited by 55 publications

(48 citation statements)

References 44 publications

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“…To evaluate the effect of the association with TMZ and amlexanox on cell viability, the CCK-8 assay was conducted. U87 MG and primary GBM cells were treated with different doses of TMZ, amlexanox, alone or both for 24, 48, and 72 h. As expected, the inhibition of proliferation in both cell types was gradually ampli ed with an increased concentration of either agent alone (Fig 1a), which was consistent with previous studies [21,4]. Moreover, the proliferation of cells treated with the combination, whether U87 MG or primary GBM cells, was e caciously attenuated (Fig 1a).…”

Section: Resultssupporting

confidence: 90%

“…The effect of TMZ or amlexanox alone on the IKBKE and AKT signaling pathways was rst evaluated. After treatment with the designated dose of either agent for 48 h in U87 MG and primary GBM cells, results were showed as Fig 4. The western blot assay indicated that TMZ induced the activation of AKT and AMPK and decreased the phosphorylation of mTOR; the activation of IKBKE was decreased after amlexanox treatment, which was consistent with previous studies [14,21,23]. After treating U87 MG and primary GBM cells with both agents, the results showed that TMZ combined with amlexanox resulted in enhanced reduction of p-AKT and p-mTOR.…”

Section: Amlexanox Promoted Tmz-induced Apoptosis Of Gbm Cellssupporting

confidence: 89%

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Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Xiong

Guo

et al. 2020

Preprint

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Background: 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 inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE), for GBM. Methods: in vitro, cell viability assay, apoptosis analysis, western blot, migration and invasion assay were used. In vivo, intracranial tumor models were constructed and the immunohistochemistry were used. Results: We found that combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration and invasion in primary glioma cell and in the human glioma cell line, U87 MG. TMZ enhanced expression of phosphoration of adenosine 5‘-monophosphate-activated protein kinase (p-AMPK) and amlexanox led to 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 inhibited phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR). In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. Conclusion: These results suggest that amlexanox sensitized primary glioma cell and U87 MG cell to TMZ at least partially though the suppression of IKBKE activation and the attenuation of AKT activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

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Section: Resultssupporting

confidence: 90%

Section: Amlexanox Promoted Tmz-induced Apoptosis Of Gbm Cellssupporting

confidence: 89%

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Xiong

Guo

et al. 2020

Preprint

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“…The research also revealed that IKKε could accelerate EMT of GBM cells . Another IKKε selective inhibitor, amlexanox was reported to generate antitumor effects by disrupting the Hippo pathway in human GBM cell lines . We guess that MCCK1 may inhibit IKKε to play anticancer role, but the regulatory mechanism of MCCK1 need to be further explored.…”

Section: Discussionmentioning

confidence: 99%

MCCK1 enhances the anticancer effect of temozolomide in attenuating the invasion, migration and epithelial‐mesenchymal transition of glioblastoma cells in vitro and in vivo

Liu

et al. 2019

Cancer Medicine

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Chemotherapy with temozolomide (TMZ) is the traditional treatment for glioblastoma (GBM). Nevertheless, majority of GBM patients have recurrence from resistance to the chemotherapy. Herein, we examined combinational effects of MCCK1 (a specific and effective IKKε inhibitor) with TMZ in GBM U251MG and U‐87MG cell lines as well as U251MG xenograft models to overcome the therapeutic limitation of chemotherapy for GBM. Although MCCK1 alone showed inhibitory effects on in vitro proliferation, migration, invasion, and EMT of U251MG and U‐87MG cells, combination of MCCK1 and TMZ showed enhanced inhibitory effects. In the U251MG GBM xenograft models, MCCK1 showed synergistic therapeutic effects in combination with TMZ to reduce tumor volumes significantly. These data indicated that MCCK1 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for GBM.

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“…Given the significant inhibitory role of YAP in innate antiviral immunity, IKKε-mediated YAP degradation relieved the repression of YAP on the innate antiviral response (50). On the contrary, another group identified IKKε to be a negative regulator of the Hippo pathway via mediating degradation of LATS1/2, suggesting a complicated role of IKKε in Hippo pathway (58) (Figure 2). cGAS-induced innate immune response was demonstrated to activate Hippo-signaling by increasing the expression of MST1 (59).…”

Section: Hippo-yap and Ifn-i Signalingmentioning

confidence: 99%

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

et al. 2020

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Recognition of pathogen-associated molecular patterns (PAMPs) triggers expression of antiviral interferons and proinflammatory cytokines, which functions as the frontier of host defense against microbial pathogen invasion. Hippo-YAP pathway regulates cell proliferation, survival, differentiation and is involved in diverse life processes, including tissue homeostasis and tumor suppression. Emerging discoveries elucidated that the components of Hippo-YAP pathway, such as MST1/2, NDR1/2, and YAP/TAZ played crucial regulatory roles in innate immunity. Meanwhile the innate immune signaling also exhibited regulatory effect on Hippo-YAP pathway. As for the importance of these two pathways, it would be interesting to figure out the deeper biological implications of their interplays. This review focuses on the regulation between Hippo-YAP pathway and innate immune signaling. We also propose the possible contribution of these interplays to tumor development.

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Amlexanox, a selective inhibitor of IKBKE, generates anti-tumoral effects by disrupting the Hippo pathway in human glioblastoma cell lines

Cited by 55 publications

References 44 publications

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

MCCK1 enhances the anticancer effect of temozolomide in attenuating the invasion, migration and epithelial‐mesenchymal transition of glioblastoma cells in vitro and in vivo

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

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