Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Stimulation of Glioma Cell Survival Is Dependent on Akt2 Function

Fortin, Shannon P.; Ennis, Matthew; Savitch, Benjamin A.; Carpentieri, David; McDonough, Wendy S.; Winkles, Jeffrey A.; Loftus, Joseph C.; Kingsley, Christopher; Hostetter, Galen; Tran, Nhan L.

doi:10.1158/1541-7786.mcr-09-0194

Cited by 55 publications

(70 citation statements)

References 45 publications

(64 reference statements)

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“…Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell survival. Depletion of AKT2 expression by siRNA abrogates TWEAKstimulated glioma cell survival, whereas no effect on glioma cell survival is observed after siRNA-mediated depletion of AKT1 expression (18). Our data suggested that down-regulation of AKT2 expression by antisense AKT2 significantly inhibited glioma cell survival through induction of apoptosis mediated by activation of NFκB and BCL2.…”

Section: Discussionmentioning

confidence: 65%

AKT2 expression is associated with glioma malignant progression and required for cell survival and invasion

Kang¹

2010

Oncol Rep

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Abstract. Recent data suggest that AKT2, one of AKT isoforms, plays an important role in tumorigenesis of human cancers. However, little evidence exists to show the mechanism of AKT2 involved in tumorigenesis. In this study, we show that AKT2 protein expression increased significantly in high grade gliomas in comparison to low grade gliomas and correlated with the expression of NFκB, BCL2, MMP2 and MMP9 by immunostaining. Further, down-regulation of AKT2 expression by antisense AKT2 induced glioma cell apoptosis mediated by NFκB and BCL2. In addition, decreased MMP2 and MMP9 expression in AKT2 knocked-down glioma cells was subsequently detected, consistent with the decreased invasion. These findings indicate that AKT2 expression is associated with more advanced and especially aggressive gliomas and critical for cell survival and invasion. IntroductionGliomas, are the most frequent primary tumors that arise in the brain. The most malignant form of glioma, glioblastoma multiforme (Grade IV), is one of the most aggressive human cancers, with a median survival of less than 1 year. Despite recent advances in cancer treatment, this statistic has not changed significantly over the past years. Therefore, it is essential to investigate the mechanism involved in the development and progression of glioma.Accumulating evidence has demonstrated that PI3K/AKT pathway is one of the important signaling pathways regulating various cellular biological processes, including growth, proliferation, survival, metabolism and motility. AKT, or protein kinase B, a serine/threonine kinase, is composed of three isoforms, AKT1, AKT2 and AKT3. Three isoforms of AKT are structurally homologous and share similar mechanisms of activation, but they also exhibit distinct features and roles (1). AKT1 and AKT2 are widely expressed, whereas AKT3 has restricted expression. Among three isoforms of AKT, AKT2 has been shown to be primarily involved in human cancer and play a central role in tumorigenesis. High expression of AKT2 has been detected in a variety of human cancers, such as laryngeal squamous cell carcinoma, breast cancer and ovarian cancer (2-4). However, there are some reports on the elevated expression of AKT2 in human gliomas (5,6), the relationship between AKT2 expression and glioma grade and the mechanism of AKT2 in gliomagenesis is still not clear.In the current study, we examined whether AKT2 expression is associated with glioma malignant progression. AKT2 expression increased significantly with the increase in pathologic grade of gliomas and correlated positively with the expression of NFκB, BCL2, MMP2 and MMP9 by immunohistochemistry (IHC). Moreover, reduction of AKT2 by antisense AKT2 inhibited glioma cell survival by induction of apoptosis mediated by NFκB and BCL2. Additionally, down-regulation of AKT2 expression suppressed cell invasion via MMP2 and MMP9. Materials and methodsPatients and samples. A glioma tissue microarray was obtained from Shanxi Chaoying Biotechnology (Xi'an, China). Pathologic grades of tumors were defined a...

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Section: Discussionmentioning

confidence: 65%

AKT2 expression is associated with glioma malignant progression and required for cell survival and invasion

Kang¹

2010

Oncol Rep

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“…Immunohistochemical Analysis of SGEF Protein-A glioma invasion tissue microarray and immunohistochemistry protocol used to examine SGEF expression in glioblastoma tumor samples has been described previously (25). A scoring system of 0, negative; 1-2, moderate; and 3, strong was used to grade the staining.…”

Section: Methodsmentioning

confidence: 99%

The Src Homology 3 Domain-containing Guanine Nucleotide Exchange Factor Is Overexpressed in High-grade Gliomas and Promotes Tumor Necrosis Factor-like Weak Inducer of Apoptosis-Fibroblast Growth Factor-inducible 14-induced Cell Migration and Invasion via Tumor Necrosis Factor Receptor-associated Factor 2

Ensign

Mathews

Eschbacher

et al. 2013

Journal of Biological Chemistry

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Background: Glioblastoma is characterized by heightened cell invasion and therapeutic resistance. Results: The Src homology 3 domain-containing GEF (SGEF) promotes fibroblast growth factor-inducible 14 (Fn14) proinvasive signaling in glioblastoma via TNF receptor-associated factor 2 (TRAF2). Conclusion: SGEF is an important regulator of glioblastoma cell invasion downstream of Fn14. Significance: Therapy directed at mediators of invasion may confer increased chemotherapeutic and radiologic susceptibility in glioblastoma.

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“…Other studies have identified TWEAK as a multifunctional cytokine involved in diverse cellular processes encompassing tissue repair and remodeling (particularly in bone and skeletal muscle; ref. [2][3][4], promotion of inflammation, cellular proliferation, angiogenesis, and cell survival (5,6). TWEAK mediates signaling through its cognate receptor fibroblast growth factor-inducible molecule 14 (Fn14), which is broadly expressed in nearly all nonhematopoietic cell types.…”

Section: Introductionmentioning

confidence: 99%

A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers

Lassen

Meulendijks

Siu

et al. 2015

Clinical Cancer Research

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Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFkB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1k monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.Experimental Design: Dose escalations, over a 200-to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics.Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t 1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258-66. Ó2014 AACR.

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Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Stimulation of Glioma Cell Survival Is Dependent on Akt2 Function

Cited by 55 publications

References 45 publications

AKT2 expression is associated with glioma malignant progression and required for cell survival and invasion

AKT2 expression is associated with glioma malignant progression and required for cell survival and invasion

A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers

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