β-Catenin Signaling Increases during Melanoma Progression and Promotes Tumor Cell Survival and Chemoresistance

Sinnberg, Tobias; Menzel, M.; Ewerth, Daniel; Sauer, Birgit; Schwarz, Michael; Schaller, Martin; Garbe, Claus; Schittek, Birgit

doi:10.1371/journal.pone.0023429

Cited by 103 publications

(106 citation statements)

References 52 publications

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“…Melanoma cell lines and cells from melanoma biopsies were tested for growth inhibition using the 4-methylumbelliferyl heptanoate (MUH) assay as described previously (21). Briefly, cells were treated with inhibitors or with DMSO (at the highest combined DMSO concentration of the inhibitors) for 72 h and were then incubated with 100 μg/ml MUH in PBS for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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Purpose NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected. Experimental design and results BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process. Conclusion The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma.

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Section: Methodsmentioning

confidence: 99%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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“…20 Constitutive activation of the Wnt/β-catenin signalling pathway is often observed in melanoma. 21,22 TIMP-2 expression modulates human melanoma cell adhesion and motility. 23 However, it is not clear how TIMP-2 directly contributes the activity of Wnt/β-catenin pathway.…”

Section: Introductionmentioning

confidence: 99%

Tissue inhibitor of metalloproteinase 2 inhibits activation of the β-catenin signaling in melanoma cells

Xia¹,

2015

Cell Cycle

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The tissue inhibitor of metalloproteinase (TIMP) family, including TIMP-2, regulates the activity of multifunctional metalloproteinases in pathogenesis of melanoma. The Wnt/β-catenin pathway is constitutively activated and plays a critical role in melanoma progression. However, the relationship between TIMP-2 expression and β-catenin activity is still unclear. We hypothesize that TIMP-2 over expression inhibits the activation of the Wnt/β-catenin pathway in melanoma cells. Protein expression, distribution, and transcriptional activity of β-catenin were assayed in established stable melanoma cell lines: parental A2058 expressing, A2058 T2-1 over-expressing (T2-1), and A2058 T2R-7 under-expressing (T2R-7) TIMP-2. Compared to T2-1 cells at the basal level, T2R-7 showed significantly lower amount protein and weaker immunofluorescence staining of β-catenin. This regulation is through posttranslational level via ubiquitination. Functionally, proliferation and cell growth were lower in T2R-7 compared to A2058 and T2-1. Lithium treatment was used to mimics activation of the Wnt/β-catenin pathway. In T2R-7 cells under-expressing TIMP2, lithium significantly increased total β-catenin, nuclear β-catenin, and its downstream protein phosphor-c-Myc (S62). Nuclear β-catenin staining was enhanced in T2R-7. Beta-catenin transcriptional activity and cell proliferation were also increased significantly. Axins inhibit β-catenin pathway via GSK-3 β. We further found the ratio of p-GSK-3 β (S9) to β-catenin and protein levels of Axins were significantly lower, whereas downstream Wnt 11 was high in T2R-7 treated with lithium. Collectively, the high level of TIMP-2 protein inhibits the activation of the Wnt/β-catenin pathway, thus suppressing proliferation. Insights in the molecular mechanisms of TIMP-2 may provide promising opportunities for anti-proliferative therapeutic intervention.

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“…Constitutive nuclear localization of b-catenin in mouse melanocytes promotes their immortalization and favors melanoma progression and invasion in an NRAS-driven melanoma model (1,2). High nuclear b-catenin levels in melanoma samples have been associated in some patients with improved survival (3); however, conflicting findings for the in vitro invasion of melanoma cells have been reported (4,5), suggesting that b-catenin may act as a pro-or anti-in vitro invasion factor.…”

Section: Introductionmentioning

confidence: 99%

β-Catenin Inhibitor ICAT Modulates the Invasive Motility of Melanoma Cells

et al. 2014

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Inhibitor of b-catenin and TCF (ICAT) inhibits b-catenin transcriptional activity by competing with T-cell factor/ lymphoid enhancer factor. We documented high ICAT levels in human melanoma cells, in which b-catenin signaling is frequently deregulated, finding a correlation with the capacity to form metastases in nude mice. Ectopic expression of ICAT in melanoma cells did not affect their proliferation but increased cell motility and Matrigel invasion of metastatic cells in a manner relying upon stable ICAT-b-catenin interaction. This effect was associated with conversion of an elongated/mesenchymal phenotype to a round/amoeboid phenotype in the absence of similar effects on elongated morphology of nonmetastatic melanoma cells. Transition from mesenchymal to amoeboid movement was associated with decreased levels of NEDD9 and activated Rac1, a positive regulator of mesenchymal movement. Ectopic ICAT promoted colonization of melanoma cells in the lungs of nude mice, suggesting an increase in metastatic potential. Together, our results showed that by downregulating Rac signaling in metastatic melanoma cells, ICAT increased their invasive motility by promoting a morphologic variation that facilitates a favorable adaptation to their microenvironment. Cancer Res; 74(7); 1983-95. Ó2014 AACR.

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β-Catenin Signaling Increases during Melanoma Progression and Promotes Tumor Cell Survival and Chemoresistance

Cited by 103 publications

References 52 publications

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Tissue inhibitor of metalloproteinase 2 inhibits activation of the β-catenin signaling in melanoma cells

β-Catenin Inhibitor ICAT Modulates the Invasive Motility of Melanoma Cells

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