Document Detail


Inhibition of proliferation and induction of apoptosis in multiple myeloma cell lines by CD137 ligand signaling.
MedLine Citation:
PMID:  20520765     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Multiple myeloma (MM) is a malignancy of terminally-differentiated plasma cells, and the second most prevalent blood cancer. At present there is no cure for MM, and the average prognosis is only three to five years. Current treatments such as chemotherapy are able to prolong a patient's life but rarely prevent relapse of the disease. Even hematopoietic stem cell transplants and novel drug combinations are often not curative, underscoring the need for a continued search for novel therapeutics. CD137 and its ligand are members of the Tumor Necrosis Factor (TNF) receptor and TNF superfamilies, respectively. Since CD137 ligand cross-linking enhances proliferation and survival of healthy B cells we hypothesized that it would also act as a growth stimulus for B cell cancers.
METHODOLOGY/PRINCIPAL FINDINGS: Proliferation and survival of B cell lymphoma cell lines were not affected or slightly enhanced by CD137 ligand agonists in vitro. But surprisingly, they had the opposite effects on MM cells, where CD137 ligand signals inhibited proliferation and induced cell death by apoptosis. Furthermore, secretion of the pro-inflammatory cytokines, IL-6 and IL-8 were also enhanced in MM but not in non-MM cell lines in response to CD137 ligand agonists. The secretion of these cytokines in response to CD137 ligand signaling was consistent with the observed activation of the classical NF-kappaB pathway. We hypothesize that the induction of this pathway results in activation-induced cell death, and that this is the underlying mechanism of CD137-induced MM cell death and growth arrest.
CONCLUSIONS/SIGNIFICANCE: These data point to a hitherto unrecognized role of CD137 and CD137 ligand in MM cell biology. The selective inhibition of proliferation and induction of cell death in MM cells by CD137 ligand agonists may also warrant a closer evaluation of their therapeutic potential.
Authors:
Charles Gullo; Liang Kai Koh; Wan Lu Pang; Kian Tong Ho; Shi Hao Tan; Herbert Schwarz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-26
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-06-03     Completed Date:  2010-09-07     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e10845     Citation Subset:  IM    
Affiliation:
Cancer Immunology Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore, Singapore.
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MeSH Terms
Descriptor/Qualifier:
4-1BB Ligand / agonists,  metabolism*
Antigens, CD137 / metabolism
Apoptosis*
B-Lymphocytes / metabolism,  pathology
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cytokines / metabolism
Humans
Inflammation Mediators / metabolism
Interleukin-2 / metabolism
Interleukin-6 / metabolism
Lymphoma / metabolism,  pathology
Multiple Myeloma / metabolism*,  pathology*
NF-kappa B / metabolism
Signal Transduction*
Chemical
Reg. No./Substance:
0/4-1BB Ligand; 0/Antigens, CD137; 0/Cytokines; 0/Inflammation Mediators; 0/Interleukin-2; 0/Interleukin-6; 0/NF-kappa B
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