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1 Induced EMT Can Occur Independently of its Pro-apoptotic Effects And Is Aided By EGF Receptor Activation
1 School of Medicine and Medical Sciences, Conway Institute, University College Dublin, Dublin, Ireland
* To whom correspondence should be addressed. E-mail: william.watson{at}ucd.ie.
Background: Apoptosis and epithelial-mesenchymal transdifferentiation (EMT) occur in stressed tubular epithelial cells and contribute to renal fibrosis.
TGF-
1 promotes these responses and we examined whether the processes were interdependent in vitro. Direct (caspase inhibition) and indirect (EGF receptor stimulation) strategies were used to block apoptosis during TGF-1 stimulation and the subsequent effect upon EMT assessed Methods: HK-2 cells were exposed to TGF-1 with or without pre-incubation with ZVAD-FMK (pan-caspase inhibitor) or concomitant treatment with EGF plus or minus pre-incubation with LY294002 (PI3-kinase inhibitor). Cells were then assessed for apoptosis and proliferation by flow cytometry, crystal violet assay and Western blotting. Markers of EMT were assessed by microscopy, immunofluorescence, real time RT-PCR, Western blotting, PAI-1 reporter assay and collagen gel contraction assay. Results: TGF-1 caused apoptosis and priming for staurosporine induced apoptosis. This was blocked by ZVAD-FMK. However, ZVAD-FMK did not prevent EMT following TGF-1 treatment. EGF inhibited apoptosis, and facilitated TGF-1 induction of EMT by increasing proliferation and accentuating E-cadherin loss. Additionally EGF significantly enhanced TGF-1 induced collagen I gel contraction. EGF increased Akt phosphorylation during EMT and the pro-survival effect of this was confirmed using LY294002, which reduced EGF induced Akt phosphorylation and reversed its anti-apoptotic and pro-proliferatory effects. Conclusion: TGF-1 induces EMT independently of its pro-apoptotic effects. TGF-1 and EGF together lead to EMT. EGF increases proliferation and resistance to apoptosis during EMT in a PI3-K Akt dependent manner. In vivo, EGF receptor activation may assist in the selective survival of a transdifferentiated, pro-fibrotic cell type.
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