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Resistance of Cutaneous Anaplastic Large-Cell Lymphoma Cells to Apoptosis by Death Ligands Is Enhanced by CD30-Mediated Overexpression of c-FLIP  Frank.

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Presentation on theme: "Resistance of Cutaneous Anaplastic Large-Cell Lymphoma Cells to Apoptosis by Death Ligands Is Enhanced by CD30-Mediated Overexpression of c-FLIP  Frank."— Presentation transcript:

1 Resistance of Cutaneous Anaplastic Large-Cell Lymphoma Cells to Apoptosis by Death Ligands Is Enhanced by CD30-Mediated Overexpression of c-FLIP  Frank K. Braun, Burkhard Hirsch, Nadya Al-Yacoub, Horst Dürkop, Chalid Assaf, Marshall E. Kadin, Wolfram Sterry, Jürgen Eberle  Journal of Investigative Dermatology  Volume 130, Issue 3, Pages (March 2010) DOI: /jid Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 Resistance of cutaneous anaplastic large-cell lymphoma (cALCL) cells to TRAIL and TNF-α. (a and b) Four cALCL cell lines (JK, Mac-1, Mac-2A, and Mac-2B) and control cells (Jurkat) were stimulated for 16hours by an agonistic anti-CD95 antibody (CH-11, 100ngml−1), by TRAIL (20ngml−1), and by TNF-α (10ngml−1). Apoptosis and cytotoxicity were determined by DNA fragmentation and lactate dehydrogenase (LDH) release, respectively (DNA fragmentation in optical density, as determined by ELISA; LDH release as percentage of Triton X–lysed controls set at 100%). Values were compared with untreated controls (C, open bars). Means±SD from individual values of at least four independent experiments are shown. (c) Four cALCL cell lines were treated with CH-11 (100ngml−1) for 8hours, DNA was stained by PI, and the hypodiploid, sub-G1 cell populations were quantified as a percentage of total cell numbers. Means±SD from three individual values of treated cells (black bars) are shown in comparison with untreated controls (open bars). (d) Representative histograms of CH-11-treated cells are shown. Percentages of apoptotic sub-G1 populations are indicated. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Full activation of the caspase cascade downstream of CD95. Processing of caspase-3, -8, -9, and -10 was analyzed by western blot analysis after stimulation of cutaneous anaplastic large-cell lymphoma cells for 16hours with the CH-11 agonistic antibody (100ngml−1), TRAIL (20ngml−1), or TNF-α (10ngml−1). Molecular weights (in kDa) are indicated for proforms and for known activated cleavage products indicated by (✄). Equal protein amounts (20μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by expression analysis of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Two experiments starting from independent cultures were performed for each cell line and yielded highly similar results. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 General expression of CD95, CD30, and TRAIL receptors but loss of TNF receptor 1. (a) Surface expression of death receptors CD95, TRAIL-R1/DR4, and TRAIL-R2/DR5 as well as of CD30 was determined by FACS analysis in cutaneous anaplastic large-cell lymphoma (cALCL) cell lines. Immunofluorescence staining with receptor-specific antibodies (filled graphs) is compared with the respective isotype controls (open graphs). The shift to the right indicates surface expression. Two experiments performed for each cell line starting from independent cultures yielded highly similar results. (b) Expression of TNFR1 as determined by western blot analysis in cALCL cell lines (JK, Mac-1, Mac-2A, and Mac-2B) was compared with that of an SzS-related cell line (HuT-78) and Jurkat cells, used as positive controls. A specific 55-kDa band was identified only in Mac-1 and the controls, whereas three other cell lines were negative. Equal amounts of protein (30μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH expression. A second experiment starting from a series of independent cultures yielded highly similar results. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 High c-FLIP expression and loss of Bid in cALCL cells. Basic protein expression, as determined by western blot analysis, is shown for caspases (3, 8, 9, and 10), caspase inhibitors (cIAP-1, cIAP-2, XIAP, survivin, and c-FLIP), and BH3-only Bcl-2 proteins (Bid, Puma, and Noxa). Expression in cALCL cell lines (JK, Mac-1, Mac-2A, and Mac-2B) is compared with that in Jurkat cells. Molecular weights are given in kDa. Identical protein amounts (30μg per lane) had been loaded in each lane, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH expression. A complete second experiment starting from a series of independent cultures yielded comparable results. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 Decreased apoptotic rates and CD95 sensitivity after CD30 stimulation. (a) Four cutaneous anaplastic large-cell lymphoma cell lines were incubated for 16hours with an agonistic anti-CD30 antibody (Ab) (Ki-1, 0.5μgml−1) and were compared with untreated controls (Cs) as well as with cells treated for 16hours with a control isotypic Ab (IgG3, 0.5μgml−1). Relative values of apoptosis as determined by DNA fragmentation (C=100%) and cytotoxicity as determined by lactate dehydrogenase release (100%=completely lysed control, Triton X-100-treated) are illustrated. (b) Cutaneous T-cell lymphoma cells were pretreated for 16hours with the Ki-1 or control isotypic Ab (IgG3, each 0.5μgml−1) followed by 8hours incubation with an agonistic anti-CD95 Ab (CH-11, 10ngml−1). Relative apoptosis and cytotoxicity values were compared with those for cells treated only with CH-11. For apoptosis, CH-11-treated cells without pretreatment were set to 100%, and for cytotoxicity, completely lysed controls (Triton X-100-treated) were set to 100%. (a and b) Mean values±SD of at least six individual values from at least three independent experiments are given. Statistical significance of differences between Ki-1 pretreated cells and IgG3 control Ab pretreated cells is indicated by asterisks (P<0.01). (c) Cleavage of caspase-8 and -3 was analyzed by western blot analysis for Mac-1 and Mac-2B cells after pre-incubation with an agonistic anti-CD30 Ab (Ki-1, 0.5μgml−1, 16hours) followed by treatment with an agonistic anti-CD95 Ab (CH-11, 10ngml−1, 8hours). Results were compared with cells left untreated, treated with Ki-1 alone, or treated with CH-11 alone, as indicated. Molecular weights of caspase proforms and cleavage products (✄) are indicated in kDa. Equal protein amounts (20μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH expression. A second experiment starting from a set of independent cell cultures yielded largely identical results. (d) The percentage of apoptotic cells (hypodiploid sub-G1 population), as quantified by flow cytometric analysis and PI staining, is illustrated for Mac-1 and Mac-2B. The cells were left untreated or treated with Ki-1 (0.5μgml−1, 24hours), with agonistic anti-CD95 Ab (CH-11, 10ngml−1, 8hours), or with both. Mean values±SD of triplicates are shown. (e) Representative histograms of Mac-2B are shown; sub-G1 populations are indicated in percentages. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

7 Figure 5 Decreased apoptotic rates and CD95 sensitivity after CD30 stimulation. (a) Four cutaneous anaplastic large-cell lymphoma cell lines were incubated for 16hours with an agonistic anti-CD30 antibody (Ab) (Ki-1, 0.5μgml−1) and were compared with untreated controls (Cs) as well as with cells treated for 16hours with a control isotypic Ab (IgG3, 0.5μgml−1). Relative values of apoptosis as determined by DNA fragmentation (C=100%) and cytotoxicity as determined by lactate dehydrogenase release (100%=completely lysed control, Triton X-100-treated) are illustrated. (b) Cutaneous T-cell lymphoma cells were pretreated for 16hours with the Ki-1 or control isotypic Ab (IgG3, each 0.5μgml−1) followed by 8hours incubation with an agonistic anti-CD95 Ab (CH-11, 10ngml−1). Relative apoptosis and cytotoxicity values were compared with those for cells treated only with CH-11. For apoptosis, CH-11-treated cells without pretreatment were set to 100%, and for cytotoxicity, completely lysed controls (Triton X-100-treated) were set to 100%. (a and b) Mean values±SD of at least six individual values from at least three independent experiments are given. Statistical significance of differences between Ki-1 pretreated cells and IgG3 control Ab pretreated cells is indicated by asterisks (P<0.01). (c) Cleavage of caspase-8 and -3 was analyzed by western blot analysis for Mac-1 and Mac-2B cells after pre-incubation with an agonistic anti-CD30 Ab (Ki-1, 0.5μgml−1, 16hours) followed by treatment with an agonistic anti-CD95 Ab (CH-11, 10ngml−1, 8hours). Results were compared with cells left untreated, treated with Ki-1 alone, or treated with CH-11 alone, as indicated. Molecular weights of caspase proforms and cleavage products (✄) are indicated in kDa. Equal protein amounts (20μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH expression. A second experiment starting from a set of independent cell cultures yielded largely identical results. (d) The percentage of apoptotic cells (hypodiploid sub-G1 population), as quantified by flow cytometric analysis and PI staining, is illustrated for Mac-1 and Mac-2B. The cells were left untreated or treated with Ki-1 (0.5μgml−1, 24hours), with agonistic anti-CD95 Ab (CH-11, 10ngml−1, 8hours), or with both. Mean values±SD of triplicates are shown. (e) Representative histograms of Mac-2B are shown; sub-G1 populations are indicated in percentages. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

8 Figure 6 CD30-mediated NF-κB activation in cutaneous T-cell lymphoma cells. (a) Activation of NF-κB pathways (canonical and alternative) is shown by western blot analysis indicating the degradation of Iκ-Bα (37kDa) at 30minutes of CD30 stimulation and processing of p100 to p52, at 16hours of CD30 stimulation of cutaneous anaplastic large-cell lymphoma cells. Equal protein amounts (12μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining and by analysis of GAPDH expression. Two experiments starting from independent cultures were performed for each cell line and yielded highly similar results. (b) Results of an analysis of nuclear translocation of p50 and p65 NF-κB subunits are shown in Mac-1 cells, after incubation with the Ki-1 antibody (0.5μgml−1, 16hours). The results determined by an NF-κB subunit ELISA had been reproduced once in an independent experiment. Values for nuclear localization of p50 and p65 (filled bars) are given as relative values according to untreated controls (open bars). (c) Inhibition of NF-κB pathways (canonical and alternative) is shown by western blot analysis for Mac-2B. Cells were pretreated with the proteasome inhibitor LLnL (4μM) or with the IKK inhibitor BMS (2μM) for 3hours followed by CD30 stimulation (Ki-1). Proteins were harvested after 30minutes for I-κBα and after 16hours for the p100/p52 analysis. Equal protein amounts (12μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining and by analysis of GAPDH expression. Two experiments starting from independent cultures were performed, which yielded highly similar results. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

9 Figure 7 CD30-mediated upregulation of c-FLIP. (a) The mRNA expression values of NF-κB target genes (c-FLIP, TRAF-1, cIAP-1, cIAP-2, and A20) were analyzed by real-time RT-PCR in four cutaneous anaplastic large-cell lymphoma (cALCL) cell lines (JK, Mac-1, Mac-2A, and Mac-2B). Cells were treated with the Ki-1 antibody (0.5μgml−1) for 16hours. Expression values were normalized by a control mRNA (hypoxanthine-guanine phosphoribosyltransferase) analyzed in parallel, and values are given as relative values according to untreated control cells. Mean values and SD of triplicates of a representative experiment (of at least two) are shown. (b) Expression of FLIPL (55kDa) was analyzed by western blot analysis in four cALCL cell lines (JK, Mac-1, Mac-2A, and Mac-2B) after treatments with an agonistic CD30 antibody (Ki-1, 0.5μgml−1), LLnL (1μM), and BMS (2μM for three cell lines; 0.1μM for Mac-1). Pretreatments with inhibitors were for 3hours, before Ki-1 was given (16hours). Equal protein amounts (20μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH expression (37kDa). An independent second experiment was performed and yielded highly comparable results. (c) Western blot analysis showing c-FLIP expression and processing in Mac-2B cells is shown after pretreatment with Ki-1 (0.5μgml−1, for 12, 16, or 20hours) followed by treatment with CH-11 (10ngml−1 for 8hours), as indicated. After CD30 stimulation, expression of the proform (55kDa) increased, which was processed to a 43-kDa fragment after CD95 stimulation. Equal protein amounts (20μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH (37kDa) expression. An independent second experiment was performed and yielded highly comparable results. (d) Western blot analysis was carried out for FADD (28kDa) and for Bid (22kDa) after treatment with Ki-1 (0.5μgml−1) for 16hours. Equal protein amounts (20μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by the analysis of GAPDH (37kDa) expression. An independent second experiment was performed and yielded highly comparable results. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

10 Figure 8 Restored CD95 sensitivity after c-FLIP knockdown. (a) A representative diagram is shown of green fluorescent protein (GFP)-expressing Mac-2B cells after c-FLIPRNAi transduction. The percentage of transduced cells (filled graph) was determined with regard to FL-1 autofluorescence (open graph). Cells counted as positive are indicated. In several independent experiments, similar results were obtained. (b) Expression of c-FLIP mRNA (RT-PCR, upper panel) and c-FLIP protein (western blot, lower panel) is shown in Mac-2B cells transduced with lentivirus (mock, ScrambleRNAi, and c-FLIPRNAi). Analysis of GAPDH (amplification and protein expression) is shown as control, and molecular weights are indicated in base pairs and kDa. Largely similar results were obtained from three independent experiments for both assays. (c) Apoptosis in Mac-2B cells is shown according to DNA fragmentation (ELISA, relative values, left) and according to the sub-G1 cell population (cell-cycle analysis, FACS, in percentage, right side). Cytotoxicity according to release of lactate dehydrogenase (LDH) had been determined in parallel but did not show large differences (data not shown). The relative apoptosis values had been normalized according to cell numbers as determined by LDH content in the extracts. Cells were transduced with c-FLIPRNAi lentivirus and compared with mock-transduced cells. Cells transduced with ScrambleRNAi showed behavior similar to that of mock-transduced cells (not shown). Treatment was with agonistic anti-CD30 antibody (Ki-1, 0.1μgml−1, 16-hour pretreatment) followed by an agonistic anti-CD95 antibody (CH-11, 10ngml−1, for additional 8hours), as indicated. Mean values±SD of triplicate values of a representative experiment are shown. Factors of Ki-1-mediated apoptosis resistance are indicated. Three independent ELISA experiments and two flow cytometry experiments were performed, which revealed similar results. (d) Expression of c-FLIP, as well as processing of caspase-8 and -3, is shown in c-FLIPRNAi and ScrambleRNAi-transduced Mac-2B cells. Treatment was with agonistic anti-CD30 antibody (Ki-1, 0.1μgml−1, 16-hour pretreatment) followed by agonistic anti-CD95 antibody (CH-11, 10ng/ml, for an additional 8hours), as indicated. Almost complete degradation of caspase-8 proform (55/53kDa) in c-FLIPRNAi-transduced cells after CH-11 treatment was obtained in two of two experiments and is indicative of complete caspase-8 processing. Experiments with mock control were done in parallel and revealed results largely similar to those of the ScrambleRNAi control (data not shown). Equal protein amounts (30μg per lane) were loaded, and consistent blotting was confirmed by Ponceau red staining as well as by analysis of GAPDH expression. A second experiment starting from an independent set of cell cultures yielded similar results. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

11 Figure 9 Expression of c-FLIP and reduced expression of Bid in cutaneous anaplastic large-cell lymphoma (cALCL) tumor cells. Two examples each of CD30, Bid, and c-FLIP expression in cALCL tumors are shown. It is noteworthy that Bid expression in large tumor cells was weaker than in small, bystander, reactive lymphocytes (arrows), whereas c-FLIP expression was moderate in tumor cells but frequently negative in reactive lymphocytes (arrows). All photographs are shown at the same magnification, indicated by the scale bar. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

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