Transforming Growth Factor-β3 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

Céline Van Themsche,Isabelle Mathieu,Sophie Parent,Eric Asselin

doi:10.1074/jbc.m608497200

Abstract

Tumor cells often acquire intrinsic resistance to the growth inhibitory and pro-apoptotic effects of transforming growth factor-beta (TGF-beta); moreover, TGF-beta can confer invasive properties to established tumor cells. In the present study, we show that TGF-beta isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) 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-beta 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-beta 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-beta 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-beta3 in tumor invasiveness.

Highlights

transforming growth factor-␤ (TGF-␤)s2 are pleiotropic cytokines that can exert tumor suppressing effects, such as growth inhibition and induction of apoptosis, as well as tumor promoting effects, such as stimulation of invasiveness, depending on cell type and cancer stage
We examined whether KLE and Hec-1A human endometrial carcinoma cell lines produced TGF-␤s and their receptors
We found that KLE cells are sensitive to the growth inhibitory effects of the different TGF-␤s, except after a prolonged exposure of 72 h when TGF-␤1 and TGF-␤3 were more potent than TGF-␤2 to suppress KLE cell proliferation (Fig. 1, C–E)

Summary

Introduction

TGF-␤s2 are pleiotropic cytokines that can exert tumor suppressing effects, such as growth inhibition and induction of apoptosis, as well as tumor promoting effects, such as stimulation of invasiveness, depending on cell type and cancer stage. We have assessed the ability of each TGF-␤ isoform to activate signaling pathways in human endometrial carcinoma cells and compared their effect on cellular proliferation, apoptosis, and invasiveness.

Results

Conclusion