FOXO3a Promotes Tumor Cell Invasion through the Induction of Matrix Metalloproteinases

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

This work was supported by grants from the Florida Department of Health, Bankhead-Coley Program (to P.S., grant FLA07BN-08), Department of Defense (to K.J.S., grant W81XH-04-1-0360), and the National Institutes of Health (to A.T., grants NCI-R01CA075134 and R01CA122099; to J.A.C., grant NCI-R01CA104505).

This publication is a collaborative work of the laboratories of P.S. and A.T. Data shown in Fig. 2C to F, 3A to F, 5A and B, and 6A and B; Fig. S1A and B, S3, S4, S6, S8, and S9 in the supplemental material; and Table 1 were generated by P.S. in the laboratory of A.T. Data shown in Fig. 1 and 7 and Fig. S1 in the supplemental material were generated by P.S. in collaboration with K.J.S. and J.A.C. in the laboratory of P.S. Data shown in Fig. 2A and B, 2G and H, 4A and B, 5C to F, and 6C and D and Fig. S1C, S2, S5, and S7 in the supplemental material were generated by H.D. in the laboratory of P.S. The manuscript was written by P.S. and A.T.

We thank Derek C. Radisky and members of the Storz laboratory for helpful discussions. We also thank Anne Brunet and Mike Greenberg for providing the FOXO3a constructs and Richard Loeser and Motoharu Seiki for providing the MMP reporter plasmids.