Inhibition of the antiproliferative effect of TGFbeta by EGF in primary human ovarian cancer cells.
The majority of ovarian cancers (OCs) arise from the ovarian surface epithelium (OSE). Proliferation of the OSE can be regulated by a number of autocrine and paracrine factors, including transforming growth factor beta (TGFbeta). Defects in the TGFbeta signaling pathway have been implicated in a number of cancers, including ovarian. We previously found that the TGFbeta signaling pathway is intact and functional in primary human OC cells, and that these cells stop growing in response to TGFbeta. Ovarian cancer cells in vivo are exposed to TGFbeta, yet continue to proliferate, therefore, mechanisms must exist to inhibit TGFbeta signaling contributing to uncontrolled cellular proliferation. Numerous signaling pathways converge with the TGFbeta pathway to modulate its effects, including signaling induced by epidermal growth factor (EGF). We hypothesized that EGF can modulate TGFbeta signaling and contribute to uncontrolled cellular proliferation of OC cells. Our results show that EGF abrogates the antiproliferative effect of TGFbeta. EGF does not modulate TGFbeta signaling by inhibiting receptor-activated Smad (R-Smad) phosphorylation or nuclear translocation. Rather, EGF decreases TGFbeta-induced mRNA expression of the cell cycle regulator, p15(INK4B), contributing to decreased sensitivity of OC cells to the antiproliferative effect of TGFbeta.
Dunfield
Lesley Deanne
LD
Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada, B3H 1X5.
Nachtigal
Mark William
MW
D021581:Active Transport, Cell Nucleus; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor