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Title: The role of caspases in lytic mechanisms of tumor necrosis factor-mediated cytolysis 
Author: Chang, Wei-Chuan
Date: 2002
Publisher: University of Hawaii at Manoa
Abstract: TNF activates several signaling pathways, some lead to cell death by apoptosis or necrosis. For our cell lines (B/C-N, 10ME, and L88.3), which represent a tumor progression model, it has not been determined whether TNF induces apoptosis or necrosis. B/C-N is not tumorigenic and represents normal cells; it is TNF-resistant. 10ME forms tumors only in immunodeficient animals and thus is intermediate on the pathway to cancer; it is TNF-sensitive. L88.3 forms tumors in normal mice and thus is cancerous; it is TNF resistant. TNF resistant cells can be rendered TNF-sensitive by addition of transcription or translation inhibitors. Recent findings indicate that TNF-induced cytolysis involves several initiator and effector caspases. Caspase comprise a family of proteases known to be involved apoptotic cell death. Thus, we investigated the correlation between TNF-mediated cytolysis and caspases activation in our cell lines. Our findings indicated that TNF induces activation of two initiator caspases (caspase-8 and caspase-9) and an effector caspase (caspase-3). Caspase-8 was activated first and may be involved in activating caspase-9. This suggests there is a link between the death receptor pathway (associated with caspase-8) and the mitochondrial pathway (associated with caspase-9). Activity levels of caspases correlated with TNF sensitivity of each cell line. TNF-induced resistance mechanisms also affect the level of caspase activities. In TNF-resistant cell lines B/C-N and L88.3, addition of a translation inhibitor caused an increase in TNF-mediated cytolysis and caspase activity. However in order to see an increase in TNF-mediated cytolysis, activity of caspase-3, -8 and -9 had to reach a threshold-level. When caspase activities were inhibited, TNF treatment activated a caspase-independent lytic pathway, perhaps involving generation of oxygen radicals or activation of phospholipase A2. In TNF-sensitive 10ME, inhibition of caspases caused a switch from apoptotic death to necrotic death in some cells. These experiments also revealed the presence of caspase-dependent and caspase-independent resistance mechanisms. Thus, the data indicate that TNF induces apoptosis through a caspase-dependent lytic mechanism. When caspase activities are inhibited, TNF induces a caspase-independent lytic mechanism. TNF also induces caspase-dependent and caspase-independent resistance mechanisms.
Description: Thesis (Ph. D.)--University of Hawaii at Manoa, 2002. Includes bibliographical references (leaves 134-151). Mode of access: World Wide Web. Also available by subscription via World Wide Web xvii, 151 leaves, bound ill. 29 cm
URI: http://hdl.handle.net/10125/3008
Rights: All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.

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