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PMID: 18354037 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma.

Blood ·Vol. 111 ·No. 10 ·2008-05-15 ·Pages 5152-62

Morales AA, Gutman D, Lee KP, Boise LH

Abstract

The use of arsenic trioxide (ATO) to treat multiple myeloma (MM) is supported by preclinical studies as well as several phase 2 studies, but the precise mechanism(s) of action of ATO has not been completely elucidated. We used gene expression profiling to determine the regulation of apoptosis-related genes by ATO in 4 MM cell lines and then focused on Bcl-2 family genes. ATO induced up-regulation of 3 proapoptotic BH3-only proteins (Noxa, Bmf, and Puma) and down-regulation of 2 antiapoptotic proteins Mcl-1 and Bcl-X(L). Coimmunoprecipitation demonstrated that Noxa and Puma bind Mcl-1 to release Bak and Bim within 6 hours of ATO addition. Bak and Bim are also released from Bcl-X(L). Silencing of Bmf, Noxa, and Bim significantly protected cells from ATO-induced apoptosis, while Puma silencing had no effect. Consistent with a role for Noxa inhibition of Mcl-1, the Bad-mimetic ABT-737 synergized with ATO in the killing of 2 MM lines. Finally, Noxa expression was enhanced by GSH depletion and inhibited by increasing GSH levels in the cells. Understanding the pattern of BH3-only protein response should aid in the rational design of arsenic-containing regimens.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics,physiology Apoptosis/drug effects Apoptosis Regulatory Proteins/genetics,physiology Arsenic Trioxide Arsenicals/pharmacology Bcl-2-Like Protein 11 Cell Death Cell Line, Tumor Gene Expression Profiling Gene Expression Regulation, Neoplastic/drug effects Humans Membrane Proteins/genetics,physiology Multiple Myeloma/drug therapy,pathology Oxides/pharmacology Proto-Oncogene Proteins/genetics,physiology Proto-Oncogene Proteins c-bcl-2/genetics,physiology
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins Arsenicals BCL2L11 protein, human BMF protein, human Bcl-2-Like Protein 11 Membrane Proteins Oxides PMAIP1 protein, human Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Arsenic Trioxide
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Morales Alejo A
Microbiology and Immunology and The Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, FL, USA.
Gutman Delia
Lee Kelvin P
Boise Lawrence H
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2007-10-116889
Published
2008-05-15
Epub
2008-00-19
Pages
5152-62
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2384139
Subset
IM
Grants
NCI NIH HHS · R01 CA097243 · United States
NCI NIH HHS · R01 CA97243 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-10-116889 PMC Full Text View journal details
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