Transforming growth factor-beta3 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.
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.
Van Themsche
Céline
C
Department of Chemistry-Biology, Université du Québec a` Trois-Rivie`res, Trois-Rivie`res, Québec G9A 5H7, Canada.
Mathieu
Isabelle
I
Department of Chemistry-Biology, Université du Québec a` Trois-Rivie`res, Trois-Rivie`res, Québec G9A 5H7, Canada.
Parent
Sophie
S
Department of Chemistry-Biology, Université du Québec a` Trois-Rivie`res, Trois-Rivie`res, Québec G9A 5H7, Canada.
Asselin
Eric
E
Department of Chemistry-Biology, Université du Québec a` Trois-Rivie`res, Trois-Rivie`res, Québec G9A 5H7, Canada. Electronic address: eric.asselin@uqtr.ca.
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D051785:Smad Proteins; D053782:Transforming Growth Factor beta3; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human