| The proteasome inhibitor bortezomib sensitizes melanoma cells toward adoptive CTL attack. | |
| | |
MedLine Citation:
|
PMID: 20179203 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Adoptive transfer of tumor-specific cytolytic T lymphocytes (CTL) results in target cell lysis by activating the intrinsic apoptotic cell death program. Not surprisingly, deregulation of the apoptotic machinery is one of the central mechanisms by which tumor cells escape immune destruction despite specific CTL recognition. Here we show that treatment with the proteasome inhibitor bortezomib sensitizes previously resistant tumor cells for cytolytic T-cell attack. Human T cells were redirected toward melanoma cells by engineered expression of an immunoreceptor with binding specificity for high molecular weight-melanoma-associated antigen. Established melanoma cell lines as well as primary melanoma cells from tumor biopsies, which are notoriously resistant toward T-cell lysis, became sensitive upon bortezomib treatment. Detailed analysis of the underlying molecular mechanism revealed that bortezomib treatment induced mitochondrial accumulation of NOXA, which potentiated the release of mitochondrial second mitochondria-derived activator of caspase (SMAC) in response to CTL effector functions, including caspase-8 and granzyme B. Our data indicate that proteasome inhibition increases the sensitivity of tumor cells toward cytolytic T-cell attack by NOXA-mediated enhancement of mitochondrial SMAC release. |
| | |
Authors:
|
Jens Michael Seeger; Patrick Schmidt; Kerstin Brinkmann; Andreas A Hombach; Oliver Coutelle; Paola Zigrino; Diana Wagner-Stippich; Cornelia Mauch; Hinrich Abken; Martin Kr?nke; Hamid Kashkar |
Related Documents
:
|
12391083 - Effect of acute hypoxia on glomus cell em and psi m as measured by fluorescence imaging. 20486623 - In vitro investigation into the potential of a mistletoe extract to alleviate adverse e... 2675283 - The rat adrenal medulla. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-02-23 |
Journal Detail:
|
Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Mar |
Date Detail:
|
Created Date: 2010-03-02 Completed Date: 2010-04-08 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
|
Languages: eng Pagination: 1825-34 Citation Subset: IM |
Affiliation:
|
Institute for Medical Microbiology, Immunology and Hygiene, Medical Faculty, University of Cologne, Cologne, Germany. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Boronic Acids
/
pharmacology* Caspase 8 / metabolism Cell Line, Tumor Combined Modality Therapy Enzyme Activation Granzymes / metabolism Humans Immunotherapy, Adoptive / methods* Intracellular Signaling Peptides and Proteins / metabolism Lymphocyte Activation / drug effects Melanoma / enzymology, genetics, immunology, therapy* Mitochondria / immunology, metabolism Mitochondrial Proteins / metabolism Proteasome Endopeptidase Complex / antagonists & inhibitors* Proto-Oncogene Proteins c-bcl-2 / immunology, metabolism Pyrazines / pharmacology* RNA, Small Interfering / administration & dosage, genetics Receptors, Cell Surface / genetics, immunology T-Lymphocytes, Cytotoxic / drug effects, immunology* Transfection X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors, immunology |
| Chemical | |
Reg. No./Substance:
|
0/Boronic Acids; 0/DIABLO protein, human; 0/Intracellular Signaling Peptides and Proteins; 0/Mitochondrial Proteins; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazines; 0/RNA, Small Interfering; 0/Receptors, Cell Surface; 0/X-Linked Inhibitor of Apoptosis Protein; 0/XIAP protein, human; 0/bortezomib; 0/carcinoembryonic antigen binding protein, human; EC 3.4.21.-/Granzymes; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.25.1/Proteasome Endopeptidase Complex |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Activation of Hedgehog signaling by the environmental toxicant arsenic may contribute to the etiolog...
Next Document: Suppression of Cyclin D1 by Hypoxia-Inducible Factor-1 via Direct Mechanism Inhibits the Proliferati...