| Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors. | |
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MedLine Citation:
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PMID: 22430632 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of β-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy. |
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Authors:
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A Ikegame; S Ozaki; D Tsuji; T Harada; S Fujii; S Nakamura; H Miki; A Nakano; K Kagawa; K Takeuchi; M Abe; K Watanabe; M Hiasa; N Kimura; Y Kikuchi; A Sakamoto; K Habu; M Endo; K Itoh; H Yamada-Okabe; T Matsumoto |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-03-20 |
Journal Detail:
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Title: Leukemia Volume: 26 ISSN: 1476-5551 ISO Abbreviation: Leukemia Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-09-05 Completed Date: 2012-11-13 Revised Date: 2013-03-04 |
Medline Journal Info:
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Nlm Unique ID: 8704895 Medline TA: Leukemia Country: England |
Other Details:
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Languages: eng Pagination: 2124-34 Citation Subset: IM |
Affiliation:
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Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, Tokushima, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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antagonists & inhibitors,
genetics,
metabolism Animals Antineoplastic Agents / therapeutic use Blotting, Western Cell Line, Tumor Cell Proliferation Flow Cytometry HLA Antigens / immunology* Humans Immunoenzyme Techniques Mice Mice, SCID Multiple Myeloma / immunology*, pathology, therapy* Neoplasm Proteins / antagonists & inhibitors, genetics, metabolism Neoplastic Stem Cells / immunology, metabolism*, pathology* RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Side-Population Cells / immunology, metabolism*, pathology Single-Chain Antibodies / immunology, therapeutic use* beta Catenin / metabolism |
| Chemical | |
Reg. No./Substance:
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0/ABCG2 protein, human; 0/Antineoplastic Agents; 0/HLA Antigens; 0/Neoplasm Proteins; 0/RNA, Messenger; 0/Single-Chain Antibodies; 0/beta Catenin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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