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J. Biol. Chem., Vol. 282, Issue 7, 4794-4802, February 16, 2007

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Transforming Growth Factor-3 Increases the Invasiveness of Endometrial Carcinoma Cells through Phosphatidylinositol 3-Kinase-dependent Up-regulation of X-linked Inhibitor of Apoptosis and Protein Kinase C-dependent Induction of Matrix Metalloproteinase-9^*

From the Department of Chemistry-Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada

Tumor cells often acquire intrinsic resistance to the growth inhibitory and pro-apoptotic effects of transforming growth factor- (TGF-); moreover, TGF- can confer invasive properties to established tumor cells. In the present study, we show that TGF- isoforms (TGF-1, TGF-2, and TGF-3) trigger proper Smad signaling in human endometrial carcinoma cell lines and efficiently inhibit cellular proliferation. These cells, however, exhibit a high degree of resistance to TGF- pro-apoptotic effects; we found that this resistant phenotype would be acquired through up-regulation of X-linked inhibitor of apoptosis protein (XIAP) levels. In addition, using RNA interference and pharmacological inhibitors, we show that TGF- increases cellular invasiveness via two distinct signaling pathways in endometrial carcinoma cells: phosphatidylinositol 3-kinase/AKT-dependent up-regulation of XIAP and protein kinase C-dependent induction of matrix-metalloproteinase-9 (MMP-9) expression. Additionally, these findings were correlated with clinical observations showing abundant TGF- immunoreactivity in human endometrial carcinoma tumors in vivo, extending from the epithelial compartment to the stroma upon acquisition of an invasive phenotype (gradually from grades I to III). Collectively our results describe for the first time a role for TGF-3 in tumor invasiveness.

Received for publication, September 5, 2006 , and in revised form, December 5, 2006.

^* This work has been supported by Canadian Institute of Health Research Grant MOP-66987. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Universitédu Québec à Trois-Rivières, 3351, Boul. des Forges, CP 500, Trois-Rivières, PQ G9A 5H7, Canada. Tel.: 819-376-5011, Ext. 3359; Fax: 819-376-5057; E-mail: eric.asselin{at}uqtr.ca.

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