Frank K Braun

Publications

• 5.54

  Impact points

  Apoptosis Induction by SAHA in Cutaneous T-Cell Lymphoma Cells Is Related to Downregulation of c-FLIP and Enhanced TRAIL Signaling.

  Nadya Al-Yacoub, Lothar F Fecker, Markus Möbs, Michael Plötz, Frank K Braun, Wolfram Sterry, Jürgen Eberle

  The Journal of investigative dermatology. 05/2012;

  Suberoylanilide hydroxamic acid (SAHA) has been approved for the treatment of cutaneous T-cell lymphoma (CTCL), but its mode of action remained largely elusive. As shown here in four CTCL cell lines, loss of cell viability correlated with significant time- and dose-dependent induction of apoptosis, ... [more] Suberoylanilide hydroxamic acid (SAHA) has been approved for the treatment of cutaneous T-cell lymphoma (CTCL), but its mode of action remained largely elusive. As shown here in four CTCL cell lines, loss of cell viability correlated with significant time- and dose-dependent induction of apoptosis, whereas cytotoxicity was less pronounced. Both extrinsic and intrinsic apoptosis pathways were activated, as seen by processing of initiator caspases 8 and 9, loss of mitochondrial membrane potential, and cytochrome c release. Characteristically, antiapoptotic mediators such as Mcl-1, XIAP, survivin, and c-FLIP were downregulated. Consistent with its critical function, c-FLIP overexpression resulted in a significant decrease of SAHA-mediated apoptosis. Enhanced sensitivity to TRAIL (TNF-related apoptosis-inducing ligand) and enhanced TRAIL signaling was seen in CTCL cell lines with high sensitivity, whereas cell lines with moderate response were characterized by downregulation of TRAIL-R2 and weaker TRAIL expression. Comparable proapoptotic responses to SAHA and to the combination with TRAIL were seen in ex vivo tumor T cells of CTCL patients. Thus, activation of extrinsic apoptosis pathways, related to c-FLIP downregulation and enhanced TRAIL signaling, appeared as characteristic for CTCL cell responsiveness to SAHA. An improved understanding of the pathways may facilitate its targeted use and the selection of suitable combinations.Journal of Investigative Dermatology advance online publication, 3 May 2012; doi:10.1038/jid.2012.125.
• 5.54

  Impact points

  Nonsteroidal anti-inflammatory drugs induce apoptosis in cutaneous T-cell lymphoma cells and enhance their sensitivity for TNF-related apoptosis-inducing ligand.

  Frank K Braun, Nadya Al-Yacoub, Michael Plötz, Markus Möbs, Wolfram Sterry, Jürgen Eberle

  The Journal of investigative dermatology. 02/2012; 132(2):429-39.

  Cutaneous T-cell lymphomas (CTCL) form a heterogeneous group of non-Hodgkin's lymphomas of the skin. In previous studies, we had characterized CTCL cells as resistant to the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which correlated to pronounced expression of... [more] Cutaneous T-cell lymphomas (CTCL) form a heterogeneous group of non-Hodgkin's lymphomas of the skin. In previous studies, we had characterized CTCL cells as resistant to the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which correlated to pronounced expression of the caspase-8/-10 inhibitor c-FLIP. For identification of proapoptotic strategies in CTCL cells and for overcoming their death ligand resistance, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid, sodium salicylate, and diclofenac (DF). These drugs strongly enhanced apoptosis, as well as decreased CTCL cell proliferation and vitality, and DF furthermore sensitized for TRAIL-induced apoptosis. Full activation of the caspase cascade (caspase-3, -8, -9) and decreased mitochondrial membrane potential were characteristic for NSAID treatment, whereas cytochrome c release was seen only for DF. Downregulation of Mcl-1 and enhanced surface expression of TRAIL were seen in response to NSAIDs. Most characteristic for apoptosis induction was the downregulation of c-FLIP. In agreement with the critical role of c-FLIP for apoptosis deficiency of CTCL cells, its overexpression decreased NSAID-mediated apoptosis and its downregulation by small hairpin RNA-enhanced apoptosis. The study provides a rationale for the use of NSAIDs as a new therapeutic option for CTCL patients. Supporting this concept, ex vivo lymphoma cells of CTCL patients also revealed significant sensitivity for NSAID treatment.
• 8.30

  Impact points

  Tumor suppressor TNFAIP3 (A20) is frequently deleted in Sézary syndrome.

  F C M Braun, P Grabarczyk, M Möbs, F K Braun, J Eberle, M Beyer, W Sterry, F Busse, J Schröder, M Delin, G K Przybylski, C A Schmidt

  Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 05/2011; 25(9):1494-501.

  Despite recent therapeutic improvements, the prognosis for patients suffering from Sézary syndrome (SS), a disseminated form of cutaneous T-cell lymphomas, is still poor. We identified bi- and monoallelic deletions of the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) in a high propor... [more] Despite recent therapeutic improvements, the prognosis for patients suffering from Sézary syndrome (SS), a disseminated form of cutaneous T-cell lymphomas, is still poor. We identified bi- and monoallelic deletions of the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) in a high proportion of SS patients as well as biallelic A20 deletion in the SS-derived cell line SeAx. Furthermore, we demonstrate that inhibition of A20 activates the NF-κB pathway thereby increasing the proliferation of normal T lymphocytes. On the other hand, the reconstitution of A20 expression slowed down the cell cycle in SeAx cells. Recently A20 inactivation has been reported in various B-cell lymphomas. In this study, we show that A20 is also a putative tumor suppressor in the T-cell malignancy-SS.
• 0.33

  Impact points

  [cFLIP diminishes CD95-induced apoptosis of CD30-stimulated cutaneous anaplastic large T cell lymphoma (cALCL) cells].

  B Hirsch, F K Braun, N Al-Yacoub, C Assaf, M E Kadin, W Sterry, J Eberle, H Dürkop

  Der Pathologe. 10/2010; 31 Suppl 2:193-8.

  Stimulation of the TNF receptors CD30 and CD95 exerts opposite effects. Crosstalk of both receptors is unknown. We aimed to reveal regulatory mechanisms of CD30-induced effects on CD95 signaling of cALCL cell lines. "CD30/CD95 crosstalk analysis" was performed in cALCL cell lines by compar... [more] Stimulation of the TNF receptors CD30 and CD95 exerts opposite effects. Crosstalk of both receptors is unknown. We aimed to reveal regulatory mechanisms of CD30-induced effects on CD95 signaling of cALCL cell lines. "CD30/CD95 crosstalk analysis" was performed in cALCL cell lines by comparison of CD30 or CD95 stimulation and CD30/CD95 costimulation. Receptor expression and induction of apoptosis was investigated by flow cytometry. mRNA expression of CD30-inducible genes (cFLIP, TRAF1, cIAP2, and A20) was compared by semiquantitative reverse transcription (RT-RQ-) PCR in stimulated and unstimulated cells. Protein expression of IκBα, p100/p52, caspase-8, caspase-3, and cFLIP was analyzed by immunoblotting. A lentiviral-based shRNA-mediated approach was used to inhibit cFLIP expression. CD30/CD95 crosstalk experiments revealed that CD30 ligation leads to NFκB-mediated cFLIP upregulation in cALCL cells, which in turn enhanced resistance to CD95-mediated apoptosis. This effect is based on the CD30-induced upregulation of cFLIP. Knockdown of cFLIP restores sensitivity to CD95-mediated apoptosis. We conclude that the anti-apoptotic function of CD30 antibodies should be kept in mind if CD30 antibody-based therapeutic concepts for ALCL lymphoma are considered.
• 5.54

  Impact points

  Enhanced death ligand-induced apoptosis in cutaneous SCC cells by treatment with diclofenac/hyaluronic acid correlates with downregulation of c-FLIP.

  Lothar F Fecker, Eggert Stockfleth, Frank K Braun, Paul M Rodust, Constanze Schwarz, Anja Köhler, Martin Leverkus, Jürgen Eberle

  The Journal of investigative dermatology. 03/2010; 130(8):2098-109.

  Actinic keratosis (AK) occurs on sun-exposed skin and may progress to invasive squamous cell carcinoma (SCC). As for its topical treatment, diclofenac/hyaluronic acid (HA) has been recently approved. The NSAID diclofenac is an inhibitor of COX-2; however, its mode of action in cutaneous epithelial c... [more] Actinic keratosis (AK) occurs on sun-exposed skin and may progress to invasive squamous cell carcinoma (SCC). As for its topical treatment, diclofenac/hyaluronic acid (HA) has been recently approved. The NSAID diclofenac is an inhibitor of COX-2; however, its mode of action in cutaneous epithelial cancer cells is largely unknown. Here, the effects of diclofenac/HA were investigated in relation to death ligand-mediated apoptosis (TNF-alpha, TRAIL, and CD95 activation). Whereas diclofenac/HA only moderately induced apoptosis by itself, it resulted in pronounced enhancement of death ligand-mediated apoptosis in sensitive SCC cell lines (3/4). Apoptosis was associated with activation of initiator caspases of the extrinsic pathway (caspase-8/caspase-10). Furthermore, death ligand and diclofenac/HA-mediated apoptosis were blocked by the same caspase inhibitors, indicating related pathways. The proapoptotic effects of diclofenac/HA appeared independent of the p53 pathway. Also, upregulation of death receptors appeared less important; however, strong downregulation of c-FLIP isoforms was seen after diclofenac/HA treatment. The crucial role of c-FLIP was proven through overexpression and knockdown experiments. Thus, induction of apoptosis appears to be highly characteristic of the mode of action of diclofenac/HA, and the therapeutic effect may be related to sensitization of neoplastic keratinocytes for death ligand-induced apoptosis.
• 5.54

  Impact points

  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

  The Journal of investigative dermatology. 11/2009;

  Death ligands, including TNF-alpha, CD95L/FasL, and TRAIL, mediate safeguard mechanisms against tumor growth and critically contribute to lymphocyte homeostasis. We investigated death receptor-mediated apoptosis and CD30/CD95 crosstalk in four CD30-positive cell lines of cutaneous anaplastic large-c... [more] Death ligands, including TNF-alpha, CD95L/FasL, and TRAIL, mediate safeguard mechanisms against tumor growth and critically contribute to lymphocyte homeostasis. We investigated death receptor-mediated apoptosis and CD30/CD95 crosstalk in four CD30-positive cell lines of cutaneous anaplastic large-cell lymphoma (cALCL). Whereas CD95 stimulation strongly induced apoptosis in cALCL cells, the pro-apoptotic pathways of TNF-alpha and TRAIL were completely blocked at an early step. Expression of TNF receptor 1 was lost in three of four cell lines, providing an explanation for TNF-alpha unresponsiveness. TRAIL resistance may be explained by the consistent overexpression of cellular flice inhibitory protein (c-FLIP) (four of four cell lines) and frequent loss of the pro-apoptotic Bcl-2 protein Bid (three of four cell lines). Changes at the receptor-expression level were largely ruled out. CD30/CD95 crosstalk experiments showed that CD30 ligation leads to NF-kappaB-mediated c-FLIP upregulation in cALCL cells, which in turn conferred enhanced resistance to CD95-mediated apoptosis. Knockdown of c-FLIP by a lentiviral approach enhanced basic apoptosis rates in cALCL cells and diminished the CD30-mediated suppression of apoptosis, thus proving the significance of c-FLIP in this context. These in vitro findings may be indicative of the clinical situation of cALCL. Further clarifying the defects in apoptosis pathways in cutaneous lymphomas may lead to improved therapies for these disorders.Journal of Investigative Dermatology advance online publication, 5 November 2009; doi:10.1038/jid.2009.299.
• 5.54

  Impact points

  Blockade of death receptor-mediated pathways early in the signaling cascade coincides with distinct apoptosis resistance in cutaneous T-cell lymphoma cells.

  Frank K Braun, Lothar F Fecker, Constanze Schwarz, Peter Walden, Chalid Assaf, Horst Dürkop, Wolfram Sterry, Jürgen Eberle

  The Journal of investigative dermatology. 11/2007; 127(10):2425-37.

  Control of apoptosis via death ligands plays a basic role for lymphocyte homeostasis and lymphoma development. In this study, cutaneous T-cell lymphoma (CTCL) cell lines revealed pronounced resistance to death ligands as compared to cell lines of T-cell acute lymphoblastic leukemia (T-ALL). The proa... [more] Control of apoptosis via death ligands plays a basic role for lymphocyte homeostasis and lymphoma development. In this study, cutaneous T-cell lymphoma (CTCL) cell lines revealed pronounced resistance to death ligands as compared to cell lines of T-cell acute lymphoblastic leukemia (T-ALL). The proapoptotic activity of tumor necrosis factor (TNF)-alpha was blocked, sensitivity to TNF-related apoptosis-inducing ligand was significantly reduced, and 1/4 CTCL cell lines was resistant to CD95 activation. In parallel, there was no activation of effector caspase-3 and initiator caspase-8 in nonresponsive CTCL cells, whereas caspase-10 was cleaved selectively in sensitive CTCL cells. No indication for a responsibility of typical downstream regulators of apoptosis was obtained, but loss of CD95 was found in 1/4, loss of TNF-R1 in 3/4, loss of caspase-10 in 2/4, loss of Bid in 1/4, and overexpression of cellular flice inhibitory protein was found in 4/4 CTCL cell lines. This clearly indicates an inhibition of apoptosis early in the extrinsic cascade, namely at the formation of the death-inducing signaling complex. Parallels with regard to expression of apoptosis regulators were seen in peripheral blood mononuclear cells and biopsies of CTCL patients. This study may indicate defects in apoptosis in CTCL and may help to guide CTCL therapy.