Down-regulation of 14-3-3ζ suppresses anchorage-independent growth of lung cancer cells through anoikis activation

doi:10.1073/pnas.0710905105

Down-regulation of 14-3-3ζ suppresses anchorage-independent growth of lung cancer cells through anoikis activation

*Department of Pharmacology and
^‡Winship Cancer Institute, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322; and
^§Institute of Structural Biology, University of Edinburgh School of Biological Sciences, Kings Buildings, Edinburgh EH9 3JR, United Kingdom

Communicated by R. John Collier, Harvard Medical School, Boston, MA, November 19, 2007 (received for review September 5, 2007)

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 14-3-3ζ in tumorigenesis through a mechanism that involves anoikis resistance. 14-3-3ζ 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 ζ 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 14-3-3ζ. This work not only reveals a critical role of 14-3-3ζ in anoikis suppression in lung cancer cells, but also identifies and validates 14-3-3ζ as a potential molecular target for anticancer therapeutic development.

Footnotes

^¶To whom correspondence should be addressed. E-mail: hfu{at}emory.edu
Author contributions: F.R.K. and H.F. designed research; Z.L., J.Z., Y.D., H.R.P., and L.B.-M. performed research; S.-Y.S. and A.A. contributed new reagents/analytic tools; Z.L., J.Z., Y.D., H.R.P., S.-Y.S., F.R.K., and H.F. analyzed data; and Z.L., F.R.K., and H.F. wrote the paper.
↵ ^†Present address: Department of Oral Pathology, School of Dentistry, Pusan National University, Pusan 602-739, South Korea.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710905105/DC1.
Freely available online through the PNAS open access option.