title: Hydrogen peroxide inhibits non-small cell lung cancer cell anoikis through the inhibition of caveolin-1 degradation.
abstract: Anoikis or detachment-induced apoptosis plays an essential role in the regulation of cancer cell metastasis. Caveolin-1 (Cav-1) is a key protein involved in tumor metastasis, but its role in anoikis and its regulation during cell detachment are unclear. We report here that Cav-1 plays a key role as a negative regulator of anoikis through a reactive oxygen species (ROS)-dependent mechanism in human lung carcinoma H460 cells. During cell detachment, Cav-1 is downregulated, whereas ROS generation is upregulated. Hydrogen peroxide and hydroxyl radical are two key ROS produced by cells during detachment. Treatment of the cells with hydrogen peroxide scavengers, catalase and N-acetylcysteine, promoted Cav-1 downregulation and anoikis during cell detachment, indicating that produced hydrogen peroxide plays a primary role in preventing anoikis by stabilizing Cav-1 protein. Catalase and N-acetylcysteine promoted ubiquitination and proteasomal degradation of Cav-1, which is a major pathway of its downregulation during cell anoikis. Furthermore, addition of hydrogen peroxide exogenously to the cells inhibited Cav-1 downregulation by preventing the formation of Cav-1-ubiquitin complex, supporting the inhibitory role of endogenous hydrogen peroxide in Cav-1 degradation during cell detachment. Together, these results indicate a novel role of hydrogen peroxide as an endogenous suppressor of cell anoikis through its stabilizing effect on Cav-1.
authors.affiliation: Dept. of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand 10330.
authors.forename: Pimuma
authors.initials: P
authors.lastname: Rungtabnapa
authors.forename: Ubonthip
authors.initials: U
authors.lastname: Nimmannit
authors.forename: Hasseri
authors.initials: H
authors.lastname: Halim
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.forename: Pithi
authors.initials: P
authors.lastname: Chanvorachote
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D023102:Anoikis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002374:Catalase / Q000627:therapeutic use*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D051242:Caveolin 1; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D002374:Catalase; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine