E2F1 induces apoptosis and sensitizes human lung adenocarcinoma cells to death-receptor-mediated apoptosis through specific downregulation of c-FLIP(short).
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.
Salon
C
C
1Groupe de Recherche sur le Cancer du Poumon, INSERM U578, Institut Albert Bonniot, La Tronche Cedex, France.
Eymin
B
B
Micheau
O
O
Chaperot
L
L
Plumas
J
J
Brambilla
C
C
Brambilla
E
E
Gazzeri
S
S
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008175:Lung Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D004247:DNA; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases