Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and ApoptosisReportar como inadecuado

Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and Apoptosis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase Met−-− oval cells are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met Metflx-flx, demonstrating that the HGF-Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Metflx-flx and Met−-− oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met−-− oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 Nox4 mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met−-− oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Metflx-flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met−-− oval cells. Interestingly, both PI3K inhibition and-or knockdown itself resulted in caspase-3 activation and loss of viability in Metflx-flx oval cells, whereas no effect was observed in Met−-− oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF-Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

Autor: Adoración Martínez-Palacián, Gaelle del Castillo, Amileth Suárez-Causado, María García-Álvaro, Diego de la Morena-Frutos,



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