This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thomas, R. K. Articles by Wolf, J. Search for Related Content PubMed PubMed Citation Articles by Thomas, R. K. Articles by Wolf, J.

(American Journal of Pathology. 2002;160:1521-1528.)
© 2002 American Society for Investigative Pathology

Regular Articles

Constitutive Expression of c-FLIP in Hodgkin and Reed-Sternberg Cells

Roman Kurt Thomas^*, Anne Kallenborn^*, Claudia Wickenhauser, Joachim Ludwig Schultze, Andreas Draube^*, Martina Vockerodt^*, Daniel Re^*, Volker Diehl^* and Jürgen Wolf^*

From the Department of Internal Medicine I^* andInstitute of Pathology, University of Cologne,Cologne, Germany; and the Department of AdultOncology, Dana-Farber Cancer Institute, andthe Department of Medicine, HarvardMedical School, Boston, Massachusetts

Crosslinking of the transmembrane receptor CD95/Fas leads to activation of a signaling cascade resulting in apoptosis. c-FLIP is a recently described protein that potently inhibits Fas-mediated apoptosis and has been shown to be a key factor in germinal center B cell survival. Because Hodgkin and Reed-Sternberg cells in classical Hodgkin’s disease (cHD) are also resistant to Fas-mediated apoptosis we studied the role of c-FLIP in classical HD. High levels of c-FLIP protein were identified in two Fas-resistant Hodgkin-derived cell lines. In contrast to other tumor cells, inhibition of protein synthesis by cycloheximide did not lead to down-regulation of c-FLIP protein in these HD cell lines. Furthermore, Fas-mediated apoptosis was only partially restored suggesting that normal regulation of c-FLIP was disrupted. The in vivo relevance of these findings was supported by demonstration of significant c-FLIP expression by immunohistochemistry in 18 of 19 evaluable cases of primary HD. Taken together, c-FLIP is constitutively expressed in HD and may therefore be a major mechanism responsible for Fas-resistance in HD.

This article has been cited by other articles:

				M. Ganapathy, R. Ghosh, X. Jianping, X. Zhang, R. Bedolla, J. Schoolfield, I-T. Yeh, D. A. Troyer, A. F. Olumi, and A. P. Kumar Involvement of FLIP in 2-Methoxyestradiol-Induced Tumor Regression in Transgenic Adenocarcinoma of Mouse Prostate Model Clin. Cancer Res., March 1, 2009; 15(5): 1601 - 1611. [Abstract] [Full Text] [PDF]

				G Kapatai and P Murray Contribution of the Epstein Barr virus to the molecular pathogenesis of Hodgkin lymphoma J. Clin. Pathol., December 1, 2007; 60(12): 1342 - 1349. [Abstract] [Full Text] [PDF]

				I. A. Mawji, C. D. Simpson, R. Hurren, M. Gronda, M. A. Williams, J. Filmus, J. Jonkman, R. S. Da Costa, B. C. Wilson, M. P. Thomas, et al. Critical Role for Fas-Associated Death Domain-Like Interleukin-1-Converting Enzyme-Like Inhibitory Protein in Anoikis Resistance and Distant Tumor Formation J Natl Cancer Inst, May 16, 2007; 99(10): 811 - 822. [Abstract] [Full Text] [PDF]

				H. Kashkar, A. Deggerich, J.-M. Seeger, B. Yazdanpanah, K. Wiegmann, D. Haubert, C. Pongratz, and M. Kronke NF-{kappa}B-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs Blood, May 1, 2007; 109(9): 3982 - 3988. [Abstract] [Full Text] [PDF]

				H. Kashkar, J.-M. Seeger, A. Hombach, A. Deggerich, B. Yazdanpanah, O. Utermohlen, G. Heimlich, H. Abken, and M. Kronke XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack Blood, November 15, 2006; 108(10): 3434 - 3440. [Abstract] [Full Text] [PDF]

				R. K. Thomas, M. L. Sos, T. Zander, O. Mani, A. Popov, D. Berenbrinker, S. Smola-Hess, J. L. Schultze, and J. Wolf Inhibition of Nuclear Translocation of Nuclear Factor-{kappa}B Despite Lack of Functional I{kappa}B{alpha} Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies Clin. Cancer Res., November 15, 2005; 11(22): 8186 - 8194. [Abstract] [Full Text] [PDF]

				D. Re, R. Kuppers, and V. Diehl Molecular Pathogenesis of Hodgkin's Lymphoma J. Clin. Oncol., September 10, 2005; 23(26): 6379 - 6386. [Abstract] [Full Text] [PDF]

				B. Boll, H. Hansen, F. Heuck, K. Reiners, P. Borchmann, A. Rothe, A. Engert, and E. Pogge von Strandmann The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis Blood, September 1, 2005; 106(5): 1839 - 1842. [Abstract] [Full Text] [PDF]

				M. Poukkula, A. Kaunisto, V. Hietakangas, K. Denessiouk, T. Katajamaki, M. S. Johnson, L. Sistonen, and J. E. Eriksson Rapid Turnover of c-FLIPshort Is Determined by Its Unique C-terminal Tail J. Biol. Chem., July 22, 2005; 280(29): 27345 - 27355. [Abstract] [Full Text] [PDF]

				D. Re, R. K. Thomas, K. Behringer, and V. Diehl From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential Blood, June 15, 2005; 105(12): 4553 - 4560. [Abstract] [Full Text] [PDF]

				J. J. F. Muris, S. A. G. M. Cillessen, W. Vos, I. S. van Houdt, J. A. Kummer, J. H. J. M. van Krieken, N. M. Jiwa, P. M. Jansen, H. C. Kluin-Nelemans, G. J. Ossenkoppele, et al. Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas Blood, April 1, 2005; 105(7): 2916 - 2923. [Abstract] [Full Text] [PDF]

				S. Poppema Immunobiology and Pathophysiology of Hodgkin Lymphomas Hematology, January 1, 2005; 2005(1): 231 - 238. [Abstract] [Full Text] [PDF]

				M. S. Ricci, Z. Jin, M. Dews, D. Yu, A. Thomas-Tikhonenko, D. T. Dicker, and W. S. El-Deiry Direct Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity Mol. Cell. Biol., October 1, 2004; 24(19): 8541 - 8555. [Abstract] [Full Text] [PDF]

				A. Dutton, J. D. O'Neil, A. E. Milner, G. M. Reynolds, J. Starczynski, J. Crocker, L. S. Young, and P. G. Murray Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death PNAS, April 27, 2004; 101(17): 6611 - 6616. [Abstract] [Full Text] [PDF]

				S. Mathas, A. Lietz, I. Anagnostopoulos, F. Hummel, B. Wiesner, M. Janz, F. Jundt, B. Hirsch, K. Johrens-Leder, H.-P. Vornlocher, et al. c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor-induced Apoptosis J. Exp. Med., April 19, 2004; 199(8): 1041 - 1052. [Abstract] [Full Text] [PDF]

				I. Schmitz, H. Weyd, A. Krueger, S. Baumann, S. C. Fas, P. H. Krammer, and S. Kirchhoff Resistance of Short Term Activated T Cells to CD95-Mediated Apoptosis Correlates with De Novo Protein Synthesis of c-FLIPshort J. Immunol., February 15, 2004; 172(4): 2194 - 2200. [Abstract] [Full Text] [PDF]

				E. M. Maggio, A. van den Berg, D. de Jong, A. Diepstra, and S. Poppema Low Frequency of FAS Mutations in Reed-Sternberg Cells of Hodgkin's Lymphoma Am. J. Pathol., January 1, 2003; 162(1): 29 - 35. [Abstract] [Full Text] [PDF]

				V. Diehl, H. Stein, M. Hummel, R. Zollinger, and J. M. Connors Hodgkin's Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease Hematology, January 1, 2003; 2003(1): 225 - 247. [Abstract] [Full Text] [PDF]