Document Detail


Merkel cell carcinoma dependence on bcl-2 family members for survival.
MedLine Citation:
PMID:  24614157     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Merkel cell carcinoma (MCC), a rare but aggressive cutaneous neoplasm with high metastatic potential, has a poor prognosis at late stages of disease with no proven chemotherapeutic regimens. Using an enriched culture medium, we established and characterized 11 MCC cell lines for Bcl-2 family profiling and functional studies. Immunoblot analysis revealed collectively high protein levels of prosurvival Bcl-2 members in cell lines and a panel of MCC tumors. Downregulation of individual Bcl-2 proteins by RNAi promoted death in a subset of MCC cell lines, whereas simultaneous inhibition of multiple family members by using the small-molecule antagonist ABT-263 led to a marked induction of cell death in 10 of 11 lines. ABT-263 induced Bax-dependent apoptosis with rapid cleavage of caspase-3 and PARP, regardless of Bcl-2 family profile or the presence of Merkel cell polyomavirus. Furthermore, ABT-263 treatment led to rapid and sustained growth suppression of MCC xenografts from a representative cell line, accompanied by a striking increase in apoptosis. Our results establish that concurrent inhibition of multiple prosurvival Bcl-2 proteins leads to effective induction of apoptosis, and strongly support the concept that targeting MCC dependence on these molecules may be useful therapeutically by reversing an intrinsic resistance to cell death.
Authors:
Monique E Verhaegen; Doris Mangelberger; Jack W Weick; Tracy D Vozheiko; Paul W Harms; Kevin T Nash; Elsa Quintana; Paul Baciu; Timothy M Johnson; Christopher K Bichakjian; Andrzej A Dlugosz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2014-03-10
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  134     ISSN:  1523-1747     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-07-17     Completed Date:  2014-09-29     Revised Date:  2014-10-03    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2241-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Aniline Compounds / pharmacology
Animals
Apoptosis / drug effects
Carcinoma, Merkel Cell / pathology*,  virology
Cell Line, Tumor
Cell Survival
Female
Humans
Male
Merkel cell polyomavirus / isolation & purification
Mice
Middle Aged
Myeloid Cell Leukemia Sequence 1 Protein / analysis
Proto-Oncogene Proteins c-bcl-2 / physiology*
Skin Neoplasms / pathology*,  virology
Sulfonamides / pharmacology
bcl-2-Associated X Protein / physiology
Grant Support
ID/Acronym/Agency:
R01 CA087837/CA/NCI NIH HHS; R01 CA087837/CA/NCI NIH HHS; T32 AR007197/AR/NIAMS NIH HHS; T32AR007197/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Aniline Compounds; 0/MCL1 protein, human; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sulfonamides; 0/bcl-2-Associated X Protein; XKJ5VVK2WD/navitoclax

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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