Document Detail


Bcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27(Kip1)-dependent G1/S cell cycle arrest in conjunction with NF-kappaB activation.
MedLine Citation:
PMID:  19447221     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
2-Methoxyestradiol (2-ME2) induces leukemia cells to undergo apoptosis in association with Bcl-2 inactivation but the mechanisms whereby Bcl-2 contributes to protection against programmed cell death in this context remain unclear. Here we showed that 2-ME2 inhibited the proliferation of Jurkat leukemia cells by markedly suppressing the levels of cyclins D3 and E, E2F1 and p21(Cip1/Waf1) and up-regulating p16(INK4A). Further, 2-ME2 induced apoptosis of Jurkat cells in association with down-regulation and phosphorylation of Bcl-2 (as mediated by JNK), up-regulation of Bak, activation of caspases-9 and -3 and PARP-1 cleavage. To determine the importance and mechanistic role of Bcl-2 in this process, we enforced its expression in Jurkat cells by retroviral transduction. Enforcing Bcl-2 expression in Jurkat cells abolished 2-ME2-induced apoptosis and instead produced a G1/S phase cell cycle arrest in association with markedly increased levels of p27(Kip1). Bcl-2 and p27(Kip1) were localized mainly in the nucleus in these apoptotic resistant cells. Interestingly, NF-kappaB activity and p50 levels were increased by 2-ME2 and suppression of NF-kappaB signaling reduced p27(Kip1) expression and sensitized cells to 2-ME2-induced apoptosis. Importantly, knocking-down p27(Kip1) in Jurkat Bcl-2 cells sensitized them to spontaneous and 2-ME2-induced apoptosis. Thus, Bcl-2 prevented the 2-ME2-induced apoptotic response by orchestrating a p27(Kip1)-dependent G1/S phase arrest in conjunction with activating NF-kappaB. Thus, we achieved a much better understanding of the penetrance and mechanistic complexity of Bcl-2 dependent anti-apoptotic pathways in cancer cells and why Bcl-2 inactivation is so critical for the efficacy of apoptosis and anti-proliferative inducing drugs like 2-ME2.
Authors:
Christina Batsi; Soultana Markopoulou; Evangelos Kontargiris; Christiana Charalambous; Christoforos Thomas; Savvas Christoforidis; Panagiotis Kanavaros; Andreas I Constantinou; Kenneth B Marcu; Evangelos Kolettas
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-03-27
Journal Detail:
Title:  Biochemical pharmacology     Volume:  78     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-05-18     Completed Date:  2009-07-08     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  33-44     Citation Subset:  IM    
Affiliation:
Cell and Molecular Physiology Unit, Laboratory of Physiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Cell Cycle / drug effects,  genetics
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinases / antagonists & inhibitors
Estradiol / analogs & derivatives*,  pharmacology
G1 Phase / drug effects,  physiology*
Humans
Jurkat Cells / cytology,  drug effects*
NF-kappa B / physiology*
Proto-Oncogene Proteins c-bcl-2 / physiology*
S Phase / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
R01 GM066882-03/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/NF-kappa B; 0/Proto-Oncogene Proteins c-bcl-2; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 50-28-2/Estradiol; 6I2QW73SR5/2-methoxyestradiol; EC 2.7.11.22/Cyclin-Dependent Kinases
Comments/Corrections

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