Document Detail


Selective induction of cell death in melanoma cell lines through targeting of Mcl-1 and A1.
MedLine Citation:
PMID:  22292048     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies.
Authors:
Daniela Senft; Carola Berking; Saskia A Graf; Claudia Kammerbauer; Thomas Ruzicka; Robert Besch
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-24
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-01-31     Completed Date:  2012-06-04     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e30821     Citation Subset:  IM    
Affiliation:
Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Cell Death / drug effects,  genetics
Cell Line, Tumor
Cells, Cultured
Gene Expression Regulation, Neoplastic / drug effects
Humans
Melanoma / drug therapy*,  genetics,  pathology*
Molecular Targeted Therapy / methods*
Primary Cell Culture
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  genetics
RNA Interference / physiology
RNA, Small Interfering / pharmacology,  therapeutic use
Skin / cytology,  drug effects
Skin Neoplasms / drug therapy*,  genetics,  pathology*
Substrate Specificity / genetics
Up-Regulation / drug effects,  genetics
Chemical
Reg. No./Substance:
0/BCL2-related protein A1; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/myeloid cell leukemia sequence 1 protein
Comments/Corrections

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