| CD40·FasL and CTLA-4·FasL fusion proteins induce apoptosis in malignant cell lines by dual signaling. | |
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MedLine Citation:
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PMID: 21088216 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Evolution of apoptosis resistance in both lymphoma and leukemia cells is well documented, and induction of apoptosis in malignant cells is a major goal of cancer therapy. Up-regulation of anti-apoptotic signals is one of the mechanisms whereby resistance to apoptosis emerges. We have previously described the fusion proteins CD40·FasL and CTLA-4·FasL, which are formed from two functional membrane proteins and induce apoptosis of activated T cells. The present study explores the potential use of CD40·FasL and CTLA-4·FasL for the killing of malignant cells of lymphatic origin. Using malignant B and T cell lines that differ in surface expression of costimulatory molecules, we found that CTLA-4·FasL induces effective apoptosis of cells expressing CD95 and activates caspases 3, 8, and 9. Only B7-expressing B cells responded to CTLA-4·FasL with rapid abrogation of cFLIP expression. CD40·FasL effectively killed only the T cells that express high levels of CD40L in addition to CD95. In these cells, CD40·FasL significantly diminished cFLIP expression. Importantly, each of the fusion proteins is more potent than its respective components parts, alone or in combination. Thus, the proteins with their two functional ends deliver a pro-apoptotic signal and, in parallel, inhibit an anti-apoptotic signal, thus optimizing the wanted, death-inducing effect. Therefore, these proteins emerge as promising agents to be used for targeted and specific tumor cell killing. |
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Authors:
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Ariel Orbach; Jacob Rachmilewitz; Noam Shani; Yonatan Isenberg; Miriam Parnas; Jui-Han Huang; Mark L Tykocinski; Michal Dranitzki-Elhalel |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-18 |
Journal Detail:
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Title: The American journal of pathology Volume: 177 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-01 Completed Date: 2011-03-15 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 3159-68 Citation Subset: AIM; IM |
Affiliation:
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Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD
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genetics,
pharmacology* Antigens, CD40 / genetics, pharmacology* Apoptosis / drug effects* CTLA-4 Antigen Cell Line, Tumor Cell Proliferation / drug effects Cells, Cultured Drug Evaluation, Preclinical Fas Ligand Protein / genetics, pharmacology* Humans Jurkat Cells Molecular Targeted Therapy Neoplasms / drug therapy, pathology* Recombinant Fusion Proteins / genetics, pharmacology* Signal Transduction / drug effects Up-Regulation / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/Antigens, CD40; 0/CTLA-4 Antigen; 0/CTLA4 protein, human; 0/Fas Ligand Protein; 0/Recombinant Fusion Proteins |
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