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 54 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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“…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

Wang

Zhou

et al. 2020

Front. Immunol.

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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, an FDA-approved anti-inflammatory drug, has been shown to inhibit GRK5 activity [39]. However, Amlexanox is a non-specific inhibitor with cross reactivity with other proteins and pathways such as IKBKE in the Hippo pathway [40]. CCG-215022, an investigational compound developed by John Tesmer's group at the University of Michigan, shows high selectivity against GRK5 [41].…”

Section: Discussionmentioning

confidence: 99%

Characterization of GRK5 as a novel regulator of rhabdomyosarcoma tumor cell growth and self-renewal

et al. 2020

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Copyright: Pham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft-tissue pediatric sarcoma. Clinical outcomes for RMS patients with relapsed or metastatic disease remain poor. Treatment options remain limited, presenting an urgent need for novel therapeutic targets. Using a high-throughput siRNA screen against the human kinome, we identified GRK5, a G-protein receptor kinase, as a novel regulator of RMS tumor cell growth and self-renewal. Through functional assays in vitro and in vivo, we show that GRK5 regulates cell cycle in a kinase-independent manner to promote RMS tumor cell growth. NFAT1 expression is regulated by GRK5 in a kinase independent manner, and loss of NFAT1 phenocopies GRK5 loss-of-function effects on the cell cycle alterations. Self-renewal of tumor propagating cells (TPCs) is thought to give rise to tumor relapse. We show that loss of GRK5 results in a significant reduction of RMS self-renewal capacity in part due to increased cell death. Treatment of human RMS xenografts in mice with CCG-215022, a GRK5-selective inhibitor, results in reduced tumor growth and self-renewal in both major subtypes of RMS. GRK5 represents a novel therapeutic target for the treatment of RMS.

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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 54 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

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

Characterization of GRK5 as a novel regulator of rhabdomyosarcoma tumor cell growth and self-renewal

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