ABSTRACT
A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Boronic Acids/pharmacology , Meningioma/metabolism , Mitochondrial Proteins/biosynthesis , Pyrazines/pharmacology , TNF-Related Apoptosis-Inducing Ligand/toxicity , Antineoplastic Agents/therapeutic use , Apoptosis/physiology , Boronic Acids/therapeutic use , Bortezomib , HEK293 Cells , Humans , Meningioma/drug therapy , Pyrazines/therapeutic use , Tumor Cells, CulturedABSTRACT
Aberrant regulation of the Wnt/ß-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or ß-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or ß-catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind ß-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or ß-catenin depend on Wnt ligands and their secretion for a sufficient level of ß-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls.
Subject(s)
Adenocarcinoma/genetics , Adenomatous Polyposis Coli Protein/genetics , Colonic Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Wnt3 Protein/genetics , beta Catenin/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenomatous Polyposis Coli Protein/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Colon/metabolism , Colon/pathology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred NOD , Mutation , Neoplasm Transplantation , Receptor, EphB2/genetics , Receptor, EphB2/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction , Wnt3 Protein/metabolism , beta Catenin/metabolismABSTRACT
Involvement in creative expression has the potential of engaging individuals in personal- and community-level change through reflection, empowerment, and the facilitation of connectedness. It is a process that can be a powerful component of community-based participatory research, as it can facilitate and support the principles of co-learning, egalitarian relationships, and respect for nonacademic knowledge. It is also a valuable means of appreciating culture and strengthening identity, which enhances health. This article reviews and discusses methods and benefits of incorporating creative expression into health promotion programs and community-based participatory research with Native Americans.