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Resistance to Fas-mediated apoptosis is restored by cycloheximide through the downregulation of cellular FLIPL in NK/T-cell lymphoma

Cited 18 time in Web of Science Cited 23 time in Scopus
Authors
Jeon, Yoon Kyung; Kim, Heejung; Park, Soo Oh; Choi, Hye Young; Kim, Young A; Park, Sung-Shin; Kim, Ji Eun; Kim, Yong Nyun; Kim, Chul-Woo
Issue Date
2005-06-01
Publisher
Nature Publishing Group
Citation
Lab Invest 2005;85:874-84.
Keywords
apoptosiscycloheximideDAP kinaseEBVFasFLIPNK/T-cell lymphoma
Abstract
Extranodal NK/T-cell lymphoma (NKTL), nasal type, is a highly aggressive neoplasm and is strongly associated with Epstein-Barr virus (EBV). In this study, we demonstrate that EBV-positive NKTL cell lines, namely, Hank-1, NK-YS, and NK-L, are resistant to Fas-mediated apoptosis induced by anti-Fas antibodies despite high levels of Fas surface expression and no mutation in the Fas gene. Fas stimulation of Hank-1 and NK-YS cells showed little processing of caspase 8, caspase 3, or bid, although the proximal signaling molecules of the death-inducing signaling complex, namely, Fas, Fas-associated protein with a death domain, caspase 8, and bid were present in these cells. Consistent with previous reports on the hypermethylation of death associated protein (DAP) kinase in NKTLs, the promoter of DAP kinase was methylated and its mRNA not detected in Hank-1 cells. However, the restoration of DAP kinase expression by 5-aza-2'-deoxycytidine did not sensitize Hank-1 to Fas-mediated apoptosis, indicating that DAP kinase deficiency does not contribute to resistance to Fas-mediated apoptosis. Since etoposide-induced apoptosis involved caspase 3 activation in Hank-1 and NK-YS cells, the caspase 3-dependent apoptotic machinery appears to be intact. Interestingly, cotreatment of Hank-1 with cycloheximide, a protein synthesis inhibitor, markedly sensitized cells to Fas-mediated apoptosis along with caspase 8 activation and c-FLIP(L) (cellular FLICE inhibitory protein long form) downregulation. Moreover, immunohistochemistry on paraffin-embedded tissue revealed c-FLIP expression in 39% (14 of 36) of NKTL patients. Taken together, these findings indicate that c-FLIP(L)-mediated resistance to Fas contributes to the development and progression of NKTLs. This study also suggests that agents capable of downregulating c-FLIP(L) could be used to treat NKTL.
ISSN
0023-6837
Language
English
URI
http://hdl.handle.net/10371/9688
DOI
https://doi.org/10.1038/labinvest.3700291
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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