Faculty Collaboration Database

Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: a paradigm shift that impacts current therapeutic strategies. J Cell Sci 2012 Sep 15;125(Pt 18):4253-63

Date

06/22/2012

Pubmed ID

22718346

Pubmed Central ID

PMC3516436

DOI

10.1242/jcs.097428

Scopus ID

2-s2.0-84872188837 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth through transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at serine473 in ATC cell lines and tissues of ATC patients, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to downregulation of CCNA1 mRNA and protein. These combined data suggest an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth through transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in tumor tissues of ATC patients. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution in relation to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways.

Author List

Marlow LA, von Roemeling CA, Cooper SJ, Zhang Y, Rohl SD, Arora S, Gonzales IM, Azorsa DO, Reddi HV, Tun HW, Döppler HR, Storz P, Smallridge RC, Copland JA

MESH terms used to index this publication - Major topics in bold

Base Sequence
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Cyclin A1
Forkhead Box Protein O3
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Gene Silencing
HEK293 Cells
Humans
Molecular Sequence Data
Promoter Regions, Genetic
Proto-Oncogene Proteins c-akt
Thyroid Carcinoma, Anaplastic
Thyroid Neoplasms
Transcription, Genetic