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Molecular and Cellular Biology, September 2009, p. 4906-4917, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00077-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

FOXO3a Promotes Tumor Cell Invasion through the Induction of Matrix Metalloproteinases{triangledown} ,{dagger}

Peter Storz,1* Heike Döppler,1 John A. Copland,1 Kaylene J. Simpson,2,{ddagger} and Alex Toker3

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Building, 4500 San Pablo Road, Jacksonville, Florida 32224,1 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115,2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 022153

Received 17 January 2009/ Returned for modification 19 February 2009/ Accepted 18 June 2009

The role of the Forkhead transcription factor FOXO3a in processes that promote tumor metastasis is poorly defined. Here, we show that depletion of FOXO3a from cancer cells leads to decreased tumor size specifically due to attenuated invasive migration. During tumor progression, an increase in tumor mass is concomitant with serum deprivation prior to tumor angiogenesis. We show that nuclear retention of FOXO3a due to serum starvation results in greatly increased cancer cell invasion. Exploration of the mechanism by which FOXO3a promotes invasive migration revealed that it induces the expression of matrix metalloproteinase 9 (MMP-9) and MMP-13, both of which have been causally linked to the invasion and progression of numerous human solid tumors. Our results link Forkhead transcription factors to a previously unexplored function in cancer progression by promoting extracellular matrix degradation, allowing tumors to invade neighboring tissues and ultimately metastasize to distant organs.

* Corresponding author. Mailing address: Mayo Clinic, Griffin Building, Rm. 306, 4500 San Pablo Road, Jacksonville, FL 32224. Phone: (904) 953-6909. Fax: (904) 953-0277. E-mail: storz.peter{at}mayo.edu

{triangledown} Published ahead of print on 29 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Peter MacCallum Cancer Centre, East Melbourne, Vic 3002, Australia.

Molecular and Cellular Biology, September 2009, p. 4906-4917, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00077-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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