1. ¹Groupe de Recherche sur le Cancer du Poumon, INSERM U578, Institut Albert Bonniot, La Tronche Cedex, France
2. ²INSERM U517, Faculté de Médecine et Pharmacie, Bd Jeanne d'Arc, Dijon, France
3. ³Etablissement Français du Sang, EFS Rhône-Alpes, CHU Michallon, La Tronche Cedex, France

Correspondence: B Eymin, Groupe de Recherche sur le Cancer du Poumon, INSERM U578, Institut Albert Bonniot, 38706 La Tronche Cedex, France. Tel: +33 476549553; Fax: +33 476549413; E-mail: Beatrice.Eymin@ujf-grenoble.fr

Received 10 February 2005; Revised 27 May 2005; Accepted 30 June 2005; Published online 29 July 2005.

Abstract

E2F1 is a transcription factor that plays a well-documented role during S phase progression and apoptosis. We had previously postulated that the low level of E2F1 in primary lung adenocarcinoma contributes to their carcinogenesis. Here, we show that E2F1 triggers apoptosis in various lung adenocarcinoma cell lines by a mechanism involving the specific downregulation of the cellular FLICE-inhibitory protein short, leading to caspase-8 activation at the death-inducing signaling complex. Importantly, we also provide evidence that E2F1 sensitizes tumor as well as primary cells to apoptosis mediated by FAS ligand or tumor necrosis factor-related apoptosis-inducing ligand, and enhances the cytotoxic effect of T lymphocytes against tumor cells. Finally, we describe the specific overexpression of c-FLIP_S in human lung adenocarcinomas with low level of E2F1. Overall, our data identify E2F1 as a critical determinant of the cellular response to death-receptor-mediated apoptosis, and suggest that its downregulation contributes to the immune escape of lung adenocarcinoma tumor cells.