title: Tumor-induced endothelial cell apoptosis: roles of NAD(P)H oxidase-derived reactive oxygen species.
abstract: Many tumor cells are capable of migrating through endothelial cell (EC) junctions and disintegrating sub-endothelial extracellular matrix to achieve extravasation. We demonstrate in this study that certain solid tumor cells can induce EC apoptosis to facilitate their escape from the circulation. The EC apoptosis is triggered by elevated intracellular reactive oxygen species (ROS) levels and direct contacts with tumor cells are required. Treating ECs with antioxidants, such as ascorbate and N-acetyl-L-cysteine (NAC), and a glutathione precursor can rescue the ECs from tumor-induced apoptosis and reduce the number of tumor cells migrating across endothelial barriers. NAD(P)H oxidase was identified as the major ROS producer in the event since inhibitors and small interference RNA specific to the enzyme could abrogate the tumor-induced ROS production and hence EC death. This study also provides evidence showing that the interaction between tumor and EC increases intracellular Ca(2+) concentration and activates protein kinase C (PKC) activity, which leads to NAD(P)H oxidase activation through the serine-phosphorylation of p47(phox) subunit. These findings suggest that blocking the tumor-induced EC apoptosis is a potential way to prevent tumor metastasis.
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Taiwan, ROC.
authors.forename: Ruei-Zeng
authors.initials: RZ
authors.lastname: Lin
authors.forename: Tsung-Pao
authors.initials: TP
authors.lastname: Wang
authors.forename: Ruei-Jiun
authors.initials: RJ
authors.lastname: Hung
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Chuang
authors.forename: Chi-Chen Michae
authors.initials: CC
authors.lastname: Chien
authors.forename: Hwan-You
authors.initials: HY
authors.lastname: Chang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012694:Serine; D013997:Time Factors; D014162:Transfection
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D012694:Serine; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011493:Protein Kinase C; D002118:Calcium