Induction of a feed forward pro-apoptotic mechanistic loop by nitric oxide in a human breast cancer model.
We have previously demonstrated that relatively high concentrations of NO [Nitric Oxide] as produced by activated macrophages induced apoptosis in the human breast cancer cell line, MDA-MB-468. More recently, we also demonstrated the importance of endogenous H2O2 in the regulation of growth in human breast cancer cells. In the present study we assessed the interplay between exogenously administered NO and the endogenously produced reactive oxygen species [ROS] in human breast cancer cells and evaluated the mechanism[s] in the induction of apoptosis. To this end we identified a novel mechanism by which NO down regulated endogenous hydrogen peroxide [H2O2] formation via the down-regulation of superoxide [O2 (.-)] and the activation of catalase. We further demonstrated the existence of a feed forward mechanistic loop involving protein phosphatase 2A [PP2A] and its downstream substrate FOXO1 in the induction of apoptosis and the synthesis of catalase. We utilized gene silencing of PP2A, FOXO1 and catalase to assess their relative importance and key roles in NO mediated apoptosis. This study provides the potential for a therapeutic approach in treating breast cancer by targeted delivery of NO where NO donors and activators of downstream players could initiate a self sustaining apoptotic cascade in breast cancer cells.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, USA. ssen@mednet.ucla.edu
Suvajit
S
Sen
Brian
B
Kawahara
Jon
J
Fukuto
Gautam
G
Chaudhuri
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D043564:Inorganic Pyrophosphatase / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D024101:Mitochondrial Proteins; D009603:Nitroso Compounds; D017382:Reactive Oxygen Species; D013481:Superoxides; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002374:Catalase; D043564:Inorganic Pyrophosphatase; C509848:PPA2 protein, human