The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells.

Abstract

Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF--but not TSP-1--stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development.

• Authors: Mahdhia Soula-Rothhut, Cyrille Coissard, Hervé Sartelet, Cédric Boudot, Georges Bellon, Laurent Martiny, Bernard Rothhut
• Journal: Experimental cell research (Exp Cell Res) Vol. 304 Issue 1 Pg. 187-201 (Mar 10 2005) ISSN: 0014-4827 [Print] United States
• PMID: 15707585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thrombospondin 1
• Tissue Inhibitor of Metalloproteinase-1
• Tumor Suppressor Proteins
• Epidermal Growth Factor
• Phosphatidylinositol 3-Kinases
• MAP Kinase Kinase 1
• Phosphoric Monoester Hydrolases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Apoptosis
• Carcinoma (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Epidermal Growth Factor (antagonists & inhibitors)
• Humans
• MAP Kinase Kinase 1 (metabolism)
• PTEN Phosphohydrolase
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoric Monoester Hydrolases (metabolism)
• Promoter Regions, Genetic
• Thrombospondin 1 (genetics, metabolism)
• Thyroid Neoplasms (metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Up-Regulation