%0 Journal Article %T Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion %+ Lipides - Nutrition - Cancer (U866) (LNC) %+ Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL) %A Aymeric, Morlé %A Carmen, Garrido %A Olivier, Micheau %Z ANR-11-LABX-0021-01-LipSTIC Labex %Z Conseil Regional de Bourgogne %Z Institut National du Cancer PLBIO14-007 %Z Ministère de la recherche %Z Ligue Nationale contre le Cancer %8 2015-02-05 %D 2015 %R 10.1038/cddis.2015.12 %Z Life Sciences [q-bio]/Biochemistry, Molecular BiologyJournal articles %X TRAIL is involved in immune tumor surveillance and is considered a promising anti-cancer agent owing to its limited side effectson healthy cells. However, some cancer cells display resistance, or become resistant to TRAIL-induced cell death. Hyperthermiacan enhance sensitivity to TRAIL-induced cell death in various resistant cancer cell lines, including lung, breast, colon or prostatecarcinomas. Mild heat shock treatment has been proposed to restore Fas ligand or TRAIL-induced apoptosis through c-FLIPdegradation or the mitochondrial pathway. We demonstrate here that neither the mitochondria nor c-FLIP degradation are requiredfor TRAIL-induced cell death restoration during hyperthermia. Our data provide evidence that insolubilization of c-FLIP, alone, issufficient to enhance apoptosis induced by death receptors. Hyperthermia induced c-FLIP depletion from the cytosolic fraction,without apparent degradation, thereby preventing c-FLIP recruitment to the TRAIL DISC and allowing efficient caspase-8 cleavageand apoptosis. Hyperthermia-induced c-FLIP depletion was independent of c-FLIP DED2 FL chain assembly motif orubiquitination-mediated c-FLIP degradation, as assessed using c-FLIP point mutants on lysine 167 and 195 or threonine 166,a phosphorylation site known to regulate ubiquitination of c-FLIP. Rather, c-FLIP depletion was associated with aggregation,because addition of glycerol not only prevented the loss of c-FLIP from the cytosol but also enabled c-FLIP recruitment within theTRAIL DISC, thus inhibiting TRAIL-induced apoptosis during hyperthermia. Altogether our results demonstrate that c-FLIP is athermosensitive protein whose targeting by hyperthermia allows restoration of apoptosis induced by TNF ligands, includingTRAIL. Our findings suggest that combining TRAIL agonists with whole-body or localized hyperthermia may be an interestingapproach in cancer therapy. %G English %2 https://inserm.hal.science/inserm-01113424/document %2 https://inserm.hal.science/inserm-01113424/file/Morle_et_a_HS_FLIP_Revision_Final.pdf %2 https://inserm.hal.science/inserm-01113424/file/4%20%28Image%20JPEG%2C%20923%C2%A0%C3%97%C2%A0Figs%201-4.pdf %2 https://inserm.hal.science/inserm-01113424/file/Figs%201-6%20Suppl.pdf %L inserm-01113424 %U https://inserm.hal.science/inserm-01113424 %~ INSERM %~ UNIV-BOURGOGNE %~ FNCLCC %~ CGFL %~ LNC-UMR866 %~ AGREENIUM %~ AGROSUP-DIJON %~ ENSBANA %~ ANR %~ TEST3-HALCNRS %~ INSTITUT-AGRO