The protein kinase IKKepsilon contributes to tumour growth and tumour pain in a melanoma model

Möser, Christine V.; Meißner, Markus; Laarmann, Kathrin; Olbrich, Katrin; King-Himmelreich, Tanya S.; Wolters, Miriam; Geißlinger, Gerd; Niederberger, Ellen

doi:10.1016/j.bcp.2015.12.016

Cited by 11 publications

(7 citation statements)

References 36 publications

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“…Previous studies have implicated IKKε in the pathology of a wide array of diseases, including cancer, inflammatory, and metabolic diseases [4,8,18]. Many studies indicate a critical role of IKKε in the pathophysiology of inflammatory diseases; it has been reported that inflammation appeared to be reduced in IKKε KO mice [19,21], and our previous study indicated that deficiency of IKKε inhibits inflammation and induces cardiac protection [7]. However, the direct effects of IKKε on AAA development are still unclear.…”

Section: Discussionmentioning

confidence: 91%

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Chai

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

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Section: Discussionmentioning

confidence: 91%

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Chai

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…PI3K/Akt1 overstimulation can also enhance NF-кB activation [10,28]. Since previous studies indicated that these proteins also constitute major IKKε/TBK1substrates [4,23,51], we wanted to clarify if the corresponding signaling pathways might contribute to melanoma cell proliferation, migration and invasion and therefore investigated the impact of amlexanox on the activation status of NF-кB p65, Akt1 and the MAP kinases ERK (p42/44) and p38 MAPK. Amlexanox significantly reduced the constitutive phosphorylation of p65 and p42/44 in SK-Mel-28 melanoma cells, indicating that these targets are involved in the anticancerogenous effects of IKKε/TBK1 inhibition, while Akt1 and p38 might only play a minor role in this context.…”

Section: Discussionmentioning

confidence: 99%

“…For this purpose, the drug and vehicle were applied 5 days/week on commercially available corn flakes in a 10% sucrose solution. The tumor volume was determined at day 4,7,9,11,14,16,18,21,23,25 and 28 with a digital caliper. The volume of the tumor was calculated with the equation "V = π/6 * 1.69 * (length * width) 1.5 ".…”

Section: Nude Mouse Xenograft Modelmentioning

confidence: 99%

“…The inhibition of IKKε in tumor cells was associated with reduced cell proliferation and resulted in the altered regulation of the NF-кB, Akt1 and MAPK pathways. The inoculation of IKKε-depleted melanoma cells in wild-type mice resulted in a significantly reduced tumor development as compared to wild-type melanoma cells [23]. In another study, IKKε-depleted mice showed a higher survival rate and less tumor development than wild-type mice after a systemic injection of melanoma cells, probably due to an increase in T-cell-mediated anti-tumor immunity [24].…”

Section: Introductionmentioning

confidence: 96%

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The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways

Möller

Wasel

Schmetzer

et al. 2020

IJMS

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Inhibitor-kappaB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IκB kinases, both described as contributors to tumor growth and metastasis in different cancer types. Several hints indicate that they are also involved in the pathogenesis of melanoma; however, the impact of their inhibition as a potential therapeutic measure in this “difficult-to-treat” cancer type has not been investigated so far. We assessed IKKε and TBK1 expression in human malignant melanoma cells, primary tumors and the metastasis of melanoma patients. Both kinases were expressed in the primary tumor and in metastasis and showed a significant overexpression in tumor cells in comparison to melanocytes. The pharmacological inhibition of IKKε/TBK1 by the approved drug amlexanox reduced cell proliferation, migration and invasion. Amlexanox did not affect the cell cycle progression nor apoptosis induction but significantly suppressed autophagy in melanoma cells. The analysis of potential functional downstream targets revealed that NF-кB and ERK pathways might be involved in kinase-mediated effects. In an in vivo xenograft model in nude mice, amlexanox treatment significantly reduced tumor growth. In conclusion, amlexanox was able to suppress tumor progression potentially by the inhibition of autophagy as well as NF-кB and MAP kinase pathways and might therefore constitute a promising candidate for melanoma therapy.

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“…The overexpression of p-Akt1 is correlated with adverse outcome in breast [12], gastric [13] and oesophageal squamous cell carcinomas [14]. In the context of melanoma, an overgrowing interest in determining as p-Akt1 acts during melanoma progression [15, 16] has been recently observed, and its inhibition has emerged as an interesting targeted therapy for these tumours [17].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylated Akt1 expression is associated with poor prognosis in cutaneous, oral and sinonasal melanomas

Soares

Morais

Carlos³

et al. 2018

Oncotarget

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Melanomas are highly aggressive tumours derived from melanocytes, which occur most commonly in the skin. Occasionally, these tumours may appear in oral and sinonasal mucous membranes. In this study, we performed a comparative analysis of the Phosphorylated Akt1 (p-Akt1) expression in 144 patients affected by cutaneous (CM), 34 oral cavity (OM), and 31 sinonasal melanomas (SNM). Similar to the metastatic cutaneous melanomas, p-Akt1 was overexpressed in 17/34 of the oral cavity and 20/31 of the sinonasal melanomas. In addition, the p-Akt1-nuclear expression was associated with poorer cancer-specific survival in cutaneous (P < .0001), oral (P < .0001), and sinonasal (P = .001) melanomas. Multivariate analysis showed p-Akt1 to be an independent prognostic marker in oral (P = .041) and sinonasal (P < .0001) melanomas patients. In conclusion, p-Akt1 overexpression is an independent prognostic marker in mucosal melanomas and is significantly up-regulated in sinonasal melanomas. As both mucosal and metastatic cutaneous melanomas showed high frequency of p-Akt1 expression, these findings suggest that mucosal melanomas have a biological behaviour, similar to the aggressive cutaneous melanomas.

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The protein kinase IKKepsilon contributes to tumour growth and tumour pain in a melanoma model

Cited by 11 publications

References 36 publications

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways

Phosphorylated Akt1 expression is associated with poor prognosis in cutaneous, oral and sinonasal melanomas

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