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Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-?-induced oxidative stress and apoptosis.

ABSTRACT: We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met(-/-) oval cells) are more sensitive to TGF-?-induced apoptosis than cells expressing a functional Met (Met(flx/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-? induced a mitochondria-dependent apoptotic cell death in Met(flx/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-?-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met(-/-) oval cells. TGF-? also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-?-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-?. 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-?-induced apoptosis and increased sensitivity of Met(flx/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 Met(flx/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-?-induced oxidative stress and apoptosis.

SUBMITTER: Martinez-Palacian A

PROVIDER: S-EPMC3534654 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis.

Martínez-Palacián Adoración A del Castillo Gaelle G Suárez-Causado Amileth A García-Álvaro María M de Morena-Frutos Diego D Fernández Margarita M Roncero Cesáreo C Fabregat Isabel I Herrera Blanca B Sánchez Aránzazu A

PloS one 20130102 1

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 (Met(flx/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 Met(flx/flx) and Met(-/-) oval cells, associated with a marke ...[more]

PMID: 23301029

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Dataset Information

Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-?-induced oxidative stress and apoptosis.

Publications

Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis.

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