Document Detail

FK228 and oncogenic H-Ras synergistically induce Mek1/2 and Nox-1 to generate reactive oxygen species for differential cell death.
MedLine Citation:
PMID:  20700043     Owner:  NLM     Status:  MEDLINE    
To investigate the mechanism behind the pro-apoptotic ability of oncogenic H-Ras to enhance FK228-induced apoptosis, we primarily used the 10T1/2-TR-H-Ras cell line, in which ectopic expression of oncogenic H-Ras(V12) is controlled by the addition of tetracycline into cultures, and secondarily used oncogenic H-Ras-expressing MCF10A cells in our studies. Our results showed the pro-apoptotic roles of Mek1/2 activation, nicotinamide adenine dinucleotide phosphate-oxidase 1 (Nox-1) elevation, and reactive oxygen species (ROS) production in FK228-induced selective cell death of oncogenic H-Ras-expressing cells versus counterpart cells. We found that although Nox-1 elevation and ROS production played essential roles in oncogenic H-Ras-induced cell proliferation and morphological transformation, the expression of oncogenic H-Ras and FK228 treatment synergistically induced activation of Mek1/2. This activation resulted in differentially increased Nox-1 elevation and ROS production leading to selective cell death of oncogenic H-Ras-expressing cells versus counterpart cells. We also found that FK228 treatment induced mitochondrial ROS and Mek1/2 activation, bypassing Raf-1, to downstream Erk1/2, participating in the induction of selective cell death. Thus, the pro-apoptotic abilities of Mek1/2 and Nox-1 should be considered as potential targets in designing therapeutic protocols using FK228 to assure ROS-mediated cell death for treating cancer cells acquiring Ras activation.
Shambhunath Choudhary; Kusum Rathore; Hwa-Chain Robert Wang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  21     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-02     Completed Date:  2010-12-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  831-40     Citation Subset:  IM    
Department of Comparative Medicine, The University of Tennessee, Knoxville, USA.
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MeSH Terms
Antibiotics, Antineoplastic / pharmacology*
Apoptosis / drug effects
Cell Proliferation
Cells, Cultured
Depsipeptides / pharmacology*
Gene Expression Regulation / drug effects
MAP Kinase Kinase 1 / metabolism
MAP Kinase Kinase 2 / metabolism
NADH, NADPH Oxidoreductases / metabolism*
Proto-Oncogene Proteins p21(ras) / metabolism
Reactive Oxygen Species / metabolism*
Tetracycline / pharmacology
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Depsipeptides; 0/Reactive Oxygen Species; 128517-07-7/romidepsin; 60-54-8/Tetracycline; EC 1.6.-/NADH, NADPH Oxidoreductases; EC 1.6.99.-/NADPH oxidase 1; EC Kinase Kinase 1; EC Kinase Kinase 2; EC Proteins p21(ras)

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