| Alteration of ceramide Synthase 6/C16-ceramide induces activating transcription factor 6-mediated ER-stress and apoptosis via perturbation of cellular Ca+2 and ER/Golgi membrane network. | |
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MedLine Citation:
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PMID: 22013072 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Mechanisms that regulate ER-stress induced apoptosis in cancer cells remain enigmatic. Recent data suggest that ceramide synthase1-6 (CerS1-6)-generated ceramides, containing different fatty acid chain lengths, might exhibit distinct and opposing functions, such as apoptosis versus survival in a context-dependent manner. Here, we investigated the mechanisms involved in the activation of one of the major ER-stress response proteins, ATF-6, and subsequent apoptosis by alterations of CerS6/C16-ceramide. Induction of wild-type (wt), but not the catalytically inactive mutant, CerS6 increased tumor growth in SCID mice, whereas siRNA-mediated knock-down of CerS6 induced ATF-6 activation and apoptosis in multiple human cancer cells. Down-regulation of CerS6/C16-ceramide, and not its further metabolism to glucosylceramide, or sphingomyelin, activated ATF-6 upon treatment with ER-stress inducers tunicamycin or SAHA. Induction of wt-CerS6 expression, but not its mutant, or ectopic expression of the dominant-negative mutant form of ATF-6, protected cells from apoptosis in response to CerS6 knock-down, and tunicamycin or SAHA treatment. Mechanistically, ATF-6 activation was regulated by a concerted two-step process, involving the release of Ca+2 from the ER stores ([Ca+2]ER), which resulted in the fragmentation of Golgi membranes in response to CerS6/C16-ceramide alteration. This resulted in the accumulation of pro-ATF-6 in the disrupted ER/Golgi membrane network, where pro-ATF6 is activated. Accordingly, ectopic expression of a Ca+2 chelator calbindin prevented the Golgi fragmentation, ATF-6 activation, and apoptosis in response to CerS6/C16-ceramide down-regulation. Overall, these data suggest a novel mechanism of how CerS6/C16-ceramide alteration activates ATF6 and induces ER-stress-mediated apoptosis in squamous cell carcinomas. |
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Authors:
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Can E Senkal; Suriyan Ponnusamy; Yefim Manevich; Marisa Meyers-Needham; Sahar A Saddoughi; Archana Mukhopadyay; Paul Dent; Jacek Bielawski; Besim Ogretmen |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-19 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Medical University of South Carolina, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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