Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis

Stel, Alja J; Cate, Bram ten; Jacobs, Sydney; Kok, Jan; Spierings, Diana C.J.; Dondorff, Monica; Helfrich, Wijnand; Kluin-Nelemans, Hanneke C.; Leij, Lou F. M. H. de; Withoff, Sebo; Kroesen, Bart-Jan

doi:10.4049/jimmunol.178.4.2287

Cited by 80 publications

(67 citation statements)

References 36 publications

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“…However, the molecular connection between JNK and fasL in our experiments was still unclear. It has recently been reported that rituximab (chimeric anti-CD20 Ab) sensitizes the non-Hodgkin lymphoma cell line to fas-induced apoptosis in association with modulation of p38 MAP kinase and NF-B (42). Further molecular studies should be conducted to elucidate how EBV-transformed B cells would be sensitized to fas-induced apoptosis following cross-linking of B7-H1.…”

Section: Discussionmentioning

confidence: 99%

Cross-Linking of B7-H1 on EBV-Transformed B Cells Induces Apoptosis through Reactive Oxygen Species Production, JNK Signaling Activation, and fasL Expression

Kim

Park

Lee

et al. 2008

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

Cross-Linking of B7-H1 on EBV-Transformed B Cells Induces Apoptosis through Reactive Oxygen Species Production, JNK Signaling Activation, and fasL Expression

Kim

Park

Lee

et al. 2008

The Journal of Immunology

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“…For instance, cotreatment with rituximab and recombinant human sTRAIL synergistically activates apoptosis (4). Analogously, we and others have recently shown that cotreatment with rituximab and an agonistic anti-Fas mAb also synergistically activates apoptosis in malignant B cells (5,6). Importantly, although clinical use of anti-Fas antibodies is deemed impossible due to liver toxicity (7)(8)(9), the potential feasibility of exploiting Fas apoptotic signaling using soluble Fas ligand (sFasL) has recently been reestablished (10,11).…”

Section: Introductionmentioning

confidence: 99%

Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists

et al. 2008

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The clinical efficacy of the CD20-specific chimeric monoclonal antibody rituximab is significantly hampered by intrinsic or acquired resistance to therapy. Rituximab activates antibodydependent cellular cytotoxicity/complement-dependent cytotoxicity-dependent lysis but also induces apoptosis by cross-linking of its target antigen CD20. Recent reports indicate that this apoptotic activity of rituximab can be synergized by cotreatment with Fas agonists. Here, we report on a strategy designed to exploit and optimize the synergy between rituximab and Fas signaling by genetically fusing a rituximab-derived antibody fragment to soluble Fas ligand (sFasL). The resultant fusion protein, designated scFvRit:sFasL, potently induced CD20-restricted apoptosis in a panel of malignant B-cell lines (10 of 11) and primary patient-derived malignant B cells (two of two non-Hodgkin lymphoma and five of six B cell chronic lymphocytic leukemia). ScFvRit:sFasL efficiently activated CD20 and Fas apoptotic signaling, resulting in a far superior proapoptotic activity compared with cotreatment with rituximab and Fas agonists. ScFvRit:sFasL lacked activity toward normal human B cells and also lacked systemic toxicity in nude mice with no elevation of aspartate aminotransferase and alanine aminotransferase levels or liver caspase-3 activity. In conclusion, scFvRit:sFasL efficiently activates CD20 and Fas-apoptotic signaling and may be useful for the elimination of malignant B cells. [Cancer Res 2008;68(2):597-604]

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“…This is in line with another recent study demonstrating the significance of ligand-independent death receptor clustering in the sensitization to Fas-mediated apoptosis and overcoming of Fas resistance. 40 Also, the observation that LY30 can sensitize Jurkat and HT29 cells to TRAIL indicates that our findings might be relevant across different tumor cell types. Taken together, this work highlights the tremendous potential of LY30 in priming tumor cells for TRAIL-mediated killing, and could have implications for the design of novel strategies to overcome the problem of TRAIL resistance in tumor cells.…”

Section: Resultsmentioning

confidence: 67%

LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization

et al. 2007

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Certain classes of tumor cells respond favorably to TRAIL due to the presence of cell surface death receptors DR4 and DR5. Despite this preferential sensitivity, resistance to TRAIL remains a clinical problem and therefore the heightened interest in identifying compounds to revert tumor sensitivity to TRAIL. We recently demonstrated that the phosphatidylinositide-3-kinase (PI3K) inhibitor, LY294002, and its inactive analog LY303511, sensitized tumor cells to vincristine-induced apoptosis, independent of PI3K/Akt pathway. Intrigued by these findings, we investigated the effect of LY303511 on TRAIL-induced apoptosis in HeLa cells. Preincubation of cells with LY30 significantly amplified TRAIL signaling as evidenced by enhanced DNA fragmentation, caspases 2, 3, 8, and 9 activation, and reduction in the tumor colony formation. This increase in TRAIL sensitivity involved mitochondrial membrane permeabilization resulting in the egress of cytochrome c and second mitochondrial activator of caspase/direct IAP-binding protein with low PI, cleavage of X-linked inhibitor of apoptosis protein, and activation of caspase 9. We link this execution signal to the ability of LY30 to downregulate cFLIP S and oligomerize DR5, thus facilitating the signaling of the death initiating signaling complex. The subsequent exposure to TRAIL resulted in processing/activation of caspase 8 and cleavage of its substrate, the BH3 protein Bid. These data provide a novel mechanism of action of this small molecule with the potential for use in TRAIL-resistant tumors. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis preferentially in tumor cells. 1,2 The selective responsiveness of TRAIL is attributed to the increased surface expression of TRAIL receptors (DR4 and DR5) on tumor cells. [3][4][5][6] In contrast, nontransformed cells express decoy receptors that provide a mechanism for evading apoptotic signaling initiated by TRAIL, and hence its tumor selectivity. 7,8 Unfortunately, as with most chemotherapeutic compounds, TRAIL-responsive tumors acquire a resistant phenotype which renders TRAIL therapy ineffective. 9,10 This has stimulated an enormous interest in identifying small molecule compounds that, when used in combination with TRAIL could sensitize tumor cells to TRAILinduced apoptosis. The desired consequence would be the need for a much lower therapeutic dose of TRAIL and at the same time an increase in the efficacy of the sensitizing drug. To that end, various groups have demonstrated that a variety of compounds and proteins (either upon silencing or upregulation) sensitize several classes of tumor cells to TRAIL-induced apoptosis. 11,12 LY303511 (LY30) is an inactive analog of LY294002 (LY29), a widely used inhibitor of the phosphatidylinositide-3-kinase (PI3K)/Akt survival pathway. 13 Previously, LY30 has been purported to have no effect on cells in contrast to its active counterpart, LY29. However, recent studies from our laboratory and other groups have demonstrated that LY30 does have a...

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Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis

Cited by 80 publications

References 36 publications

Cross-Linking of B7-H1 on EBV-Transformed B Cells Induces Apoptosis through Reactive Oxygen Species Production, JNK Signaling Activation, and fasL Expression

Cross-Linking of B7-H1 on EBV-Transformed B Cells Induces Apoptosis through Reactive Oxygen Species Production, JNK Signaling Activation, and fasL Expression

Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists

LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization

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