Down-regulation of 14-3-3zeta suppresses anchorage-independent growth of lung cancer cells through anoikis activation.
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.
Li
Zenggang
Z
Department of Pharmacology and Winship Cancer Institute, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
Zhao
Jing
J
Du
Yuhong
Y
Park
Hae Ryoun
HR
Sun
Shi-Yong
SY
Bernal-Mizrachi
Leon
L
Aitken
Alastair
A
Khuri
Fadlo R
FR
Fu
Haian
H
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
D048948:14-3-3 Proteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2