Abstract
ObjectiveThe tumor necrosis factor (TNF) and the cellular NF-κB pathway protein IKKβ play important roles in various cellular processes such as cell proliferation, survival, differentiation, and apoptosis. A heat shock protein 90 inhibitor, 17-DMAG, can induce apoptosis of some tumor cells. This study is to determine the combined effects of 17-DMAG and TNF on malignant cells and the related mechanisms.MethodsWe have determined effects of 17-DMAG, an Hsp90 inhibitor, and TNF treatments on the small cell lung cancer cell line (MS-1), the adenocarcinoma cell line (A549), the squamous-cell carcinoma cell line (LK-2), and the normal human bronchial epithelium cell line (NuLi-1) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrozolium bromide assay. To determine if 17-DMAG inhibit the expression of IKKβ in the normal human NuLi-1 cells, and the malignant MS-1, A549, and LK-2 cells, immunoblotting assays and luciferase assays were performed.ResultsIt was found that the combined treatments resulted in synergistic killing of malignant cells, which was confirmed by the apoptosis determination using a fluorescence microscopic assay following staining of the drug-treated cells with Hoescht 33258. The immunoblotting results indicated that the synergistic killing due to 17-DMAG and TNF treatments may be related to the decreases in IKKβ levels in the presence of 17-DMAG.ConclusionsThe results suggest that combination of 17-DMAG and TNF treatments might be useful for treating malignancies upon further study in the further.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2041198513886824
Highlights
Heat shock proteins (Hsps) are a group of chaperones that are important in maintaining stability and function of their client proteins
It is indicated that such a synergistic killing may be related to the decreases in IKKβ levels in the presence of 17-DMAG
Our results suggest that combination of 17-DMAG and tumor necrosis factor (TNF) might be useful for treating malignancies upon further study in the further
Summary
Heat shock proteins (Hsps) are a group of chaperones that are important in maintaining stability and function of their client proteins. Heat shock protein 90 (Hsp90) regulates stability, degradation, translation, and function of its client proteins, via an ATP-regulated mechanism [1]. The tumor necrosis factor (TNF) plays important roles in various cellular processes such as cell proliferation, survival, differentiation, and apoptosis [9]. Since TNF can induce apoptosis of cells, it may be a potential therapeutic agent to treat cells. TNF induces multiple pathways including cell proliferation and survival processes that may facilitate tumor development [10]. Novel reagents are necessary to inhibit TNF-induced survival signals, possibly by resulting in a synergistic effect on malignant cells
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