title: The n3-polyunsaturated fatty acid docosahexaenoic acid induces immunogenic cell death in human cancer cell lines via pre-apoptotic calreticulin exposure.
abstract: Some anticancer chemotherapeutics, such as anthracyclines and oxaliplatin, elicit immunogenic apoptosis, meaning that dying cancer cells are engulfed by dendritic cells and tumor antigens are efficiently presented to CD8+ T cells, which control residual tumor cells. Immunogenic apoptosis is characterized by pre-apoptotic cell surface exposure of calreticulin (CRT), which usually resides into the endoplasmic reticulum. We investigated the ability of the n3-polyunsaturated fatty acid docosahexaenoic acid (22:6n3, DHA) to induce pre-apoptotic CRT exposure on the surface of the human PaCa-44 pancreatic and EJ bladder cancer cell lines. Cells were treated with 150 μM DHA for different time periods, and, by immunoblot and immunofluorescence, we showed that DHA induced CRT exposure, before the apoptosis-associated phosphatidylserine exposure. As for the known immunogenic compounds, CRT exposure was inhibited by the antioxidant GSH, the pan-caspase zVAD-FMK, and caspase-8 IETD-FMK inhibitor. We provide the first evidence that DHA induces CRT exposure, representing thus a novel potential anticancer immunogenic chemotherapeutic agent.
authors.affiliation: Department of Ecological and Biological Sciences, Tuscia University, Largo dell'Università, Blocco C, 01100 Viterbo, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Molinari
authors.forename: Donatella
authors.initials: D
authors.lastname: D'Eliseo
authors.forename: Laura
authors.initials: L
authors.lastname: Manzi
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
authors.forename: Francesca
authors.initials: F
authors.lastname: Velotti
authors.forename: Nicolò
authors.initials: N
authors.lastname: Merendino
mesh_terms: D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D037282:Calreticulin / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002469:Cell Separation; D004281:Docosahexaenoic Acids / Q000276:immunology / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting
chemical_list: D000970:Antineoplastic Agents; D037282:Calreticulin; D004281:Docosahexaenoic Acids