Document Detail

The proteasome inhibitor bortezomib sensitizes melanoma cells toward adoptive CTL attack.
MedLine Citation:
PMID:  20179203     Owner:  NLM     Status:  MEDLINE    
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.
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 :
14739993 - Prohibitins and ras2 protein cooperate in the maintenance of mitochondrial function dur...
16730343 - Mitochondrial regulation of apoptotic cell death.
6332363 - Defective responses to lipid a in c3h/hej mice: approaches to an understanding of lipid...
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    
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
Boronic Acids / pharmacology*
Caspase 8 / metabolism
Cell Line, Tumor
Combined Modality Therapy
Enzyme Activation
Granzymes / metabolism
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*
X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors,  immunology
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 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...