Cyclo-oxygenase 2 expression impairs serum-withdrawal-induced apoptosis in liver cells

Amalia Fernández-Martínez , Belén Mollá , Rafael Mayoral , Lisardo Boscá , Marta Casado , Paloma Martín-Sanz , Paloma Martín-Sanz (1)

1 Inflammation

We have investigated the mechanism of COX-2-dependent inhibition of apoptosis in liver, a key pathway underlying proliferative actions of COX-2 in liver cancers, cirrhosis, chronic hepatitis C infection, and regeneration after partial hepatectomy. Stable expression of COX-2 in Chang Liver (CHL) cells induced proliferation, with an increase in the proportion of cells in S phase but no other significant changes on cell-cycle distribution. This was associated with a marked inhibition of the apoptotic response to serum deprivation, an effect mimicked by treating empty-vector transfected controls (CHL-V) with prostaglandin E 2}, and prevented in COX-2 expressing cells (CHL-C) treated with selective inhibitors of COX-2. Serum-deprived CHL-V cells displayed several indicators of activation of intrinsic apoptosis: caspases 9 and 3 activated within 6 h and caspase 8 within 18 h, Bax expression was induced, cytochrome c was released to the cytosol, and PARP-1 cleavage was evident in nuclei. COX-2 expression blocked these events, concomitant with reduced expression of p53 and promotion of Akt phosphorylation, the latter indicating activation of survival pathways. CHL were resistant to stimulation of the extrinsic pathway with anti-Fas antibody. Moreover, in vivo expression of GFP-labelled COX-2 in mice by hydrodynamics-based transient transfection conferred resistance to caspase 3 activation and apoptosis induced by stimulation of Fas.

Mots clés: Life Sciences

Amalia Fernández-Martínez, Belén Mollá, Rafael Mayoral, Lisardo Boscá, Marta Casado, et al.. Cyclo-oxygenase 2 expression impairs serum-withdrawal-induced apoptosis in liver cells. Biochemical Journal, 2006, 398 (3), pp.371-380. ⟨10.1042/BJ20060780⟩. ⟨hal-00478607⟩