title: Down-regulation of 14-3-3zeta suppresses anchorage-independent growth of lung cancer cells through anoikis activation.
abstract: The family of 14-3-3 proteins has emerged as critical regulators of diverse cellular responses under both physiological and pathological conditions. Here, we report an important role of 14-3-3zeta in tumorigenesis through a mechanism that involves anoikis resistance. 14-3-3zeta is up-regulated in a number of cancer types, including lung cancer. Through an RNAi approach using human lung adenocarcinoma-derived A549 cells as a model system, we have found that knockdown of a single zeta isoform of 14-3-3 is sufficient to restore the sensitivity of cancer cells to anoikis and impair their anchorage-independent growth. Enhanced anoikis appears to be mediated in part by up-regulated BH3-only proteins, Bad and Bim, coupled with decreased Mcl-1, resulting in the subsequent activation of Bax. This study suggests a model in which anchorage-independent growth of lung cancer cells requires the presence of 14-3-3zeta. This work not only reveals a critical role of 14-3-3zeta in anoikis suppression in lung cancer cells, but also identifies and validates 14-3-3zeta as a potential molecular target for anticancer therapeutic development.
authors.affiliation: Department of Pharmacology and Winship Cancer Institute, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Zenggang
authors.initials: Z
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Hae Ryoun
authors.initials: HR
authors.lastname: Park
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Leon
authors.initials: L
authors.lastname: Bernal-Mizrachi
authors.forename: Alastair
authors.initials: A
authors.lastname: Aitken
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D048948:14-3-3 Proteins / Q000096:biosynthesis*; D000230:Adenocarcinoma; D023102:Anoikis; D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2