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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis / drug effects
-
Apoptosis / genetics
-
Cell Line, Tumor
-
Endometrial Neoplasms / genetics
-
Endometrial Neoplasms / metabolism*
-
Endometrial Neoplasms / pathology
-
Enzyme Inhibitors / pharmacology
-
Female
-
Gene Expression Regulation, Enzymologic / drug effects*
-
Gene Expression Regulation, Enzymologic / genetics
-
Gene Expression Regulation, Neoplastic / drug effects*
-
Gene Expression Regulation, Neoplastic / genetics
-
Humans
-
Matrix Metalloproteinase 9 / biosynthesis*
-
Matrix Metalloproteinase 9 / genetics
-
Neoplasm Invasiveness
-
Phosphatidylinositol 3-Kinases / genetics
-
Phosphatidylinositol 3-Kinases / metabolism*
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase C / antagonists & inhibitors
-
Protein Kinase C / genetics
-
Protein Kinase C / metabolism*
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism
-
RNA Interference
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Smad Proteins / genetics
-
Smad Proteins / metabolism
-
Transforming Growth Factor beta3 / genetics
-
Transforming Growth Factor beta3 / metabolism
-
Transforming Growth Factor beta3 / pharmacology*
-
Up-Regulation / drug effects
-
Up-Regulation / genetics
-
X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors
-
X-Linked Inhibitor of Apoptosis Protein / genetics
-
X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
-
Enzyme Inhibitors
-
Phosphoinositide-3 Kinase Inhibitors
-
Smad Proteins
-
Transforming Growth Factor beta3
-
X-Linked Inhibitor of Apoptosis Protein
-
XIAP protein, human
-
Proto-Oncogene Proteins c-akt
-
Protein Kinase C
-
Matrix Metalloproteinase 9