Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways

Abstract

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.

Targeting TBK1 Inhibits Migration and Resistance to MEK Inhibitors in Mutant NRAS Melanoma

“…Conversely, the expression of TBK1-myr in some cell lines led to an increase in migratory and invasive properties. Consistent with our findings, other groups have recently implicated TBK1 in glioblastoma and lung carcinoma cell migration, as assessed by wound healing assays (40, 41). …”

Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis

“…Finally, we assayed the function of two TRA2β-regulated isoforms, TANK+ex3 and CCDC88C+ex26 , both included at higher levels in MDA-MB231 and breast tumors with TRA2β-high levels (Figures 6D-6F). Both TANK and CCDC88C genes were implicated in cell invasion (Ishida-Takagishi et al, 2012; Stellzig et al, 2013), although the function of these specific isoforms had yet to be characterized. MDA-MB231 cells expressing isoform-specific shRNAs targeting the TANK+ex3 isoform formed smaller and less invasive structures than control cells (TANK+ex3 sh +DOX versus −DOX), at least partially recapitulating the phenotype of TRA2β-KD (Figures S6E-S6G).…”

“…In MDA-MB231 cells, TRA2β controls the AS of target genes associated with cell invasion, Wnt signaling, cell polarity, cell cycle, and transcriptional control. For example, high TRA2β levels in both TNBC cells and human tumors are associated with the AS of TANK , a member of the tumor necrosis factor receptor-associated factor protein family, which has been linked with cell proliferation and migration in brain tumors (Stellzig et al, 2013). The inclusion of TANK exon 3 encodes 58 additional amino acids in the N-terminal domain, which could affect the function of the protein.…”

Epigenetic therapy of novel tumour suppressor ZAR1 and its cancer biomarker function

“…FTC-133 [59], Hep2 [60], Hep2G [61], A549 [62], HCT116wt, and HCT116delp53 were obtained from Thorsten Stiewe [63]. RD [64, 65], germ cell carcinoma [66], malignant melanoma cell lines [67], kidney cancer cell lines [60], breast cancer cell lines [57], glioblastoma cell lines were obtained from Lienhard Schmitz [68], ovarian carcinoma samples, and control patient material; and all patients signed informed consent before enrolment [69]. The study was approved by local ethic committees [69].…”