{"id":{"repo_id":"cagliari","oai_identifier":"oai:iris.unica.it:11584/474587"},"canonical_url":"https://search.dev.ndltd.org/etd/cagliari/oai:iris.unica.it:11584/474587","repository":{"repo_id":"cagliari","name":"Università di Cagliari","base_url":"https://iris.unica.it/oai/request"},"display":{"title":"Oleoylethanolamide and palmitoylethanolamide synergize with IFNβ to potentiate apoptosis and PD-L1 induction in SH-SY5Y neuroblastoma cells","abstract":"Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous bioactive lipids that act as selective agonists of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor implicated in lipid metabolism, inflammation, and cancer biology. While their anti-tumour potential has been suggested in various malignancies, their role in human neuroblastoma (NB) remains unexplored. NB, a paediatric solid tumour with poor prognosis in aggressive forms, may benefit from novel therapeutic strategies that exploit molecular vulnerabilities and enhance the efficacy of existing treatments. Type I interferons (IFNs), particularly IFNβ, are cytokines with well-characterized antiviral and anti-proliferative actions and documented capacity to trigger apoptosis in tumour cells, including NB. In this study, we investigated whether OEA and PEA could modulate IFNβ-induced responses in human SHSY5Y NB cells. Through a combination of viability assays, scratch wound healing, clonogenic assays, and western blotting, we show that OEA and PEA significantly enhance IFNβ-mediated cytotoxicity. Co-treatment with IFNβ and either lipid potentiated apoptosis, as indicated by increased cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP), together with reduced levels of survivin, a protein involved in anti-apoptotic regulation. Importantly, this effect occurred without amplifying canonical IFNβ signalling through the JAK-STAT pathway or PKR induction, suggesting a parallel and complementary apoptotic mechanism. Furthermore, OEA and PEA enhanced IFNβ-induced PD-L1 expression both in whole-cell lysates and on the plasma membrane. Pharmacological inhibition and the genetic silencing of PPARα attenuated PARP cleavage and PD-L1 upregulation, confirming the receptor’s contribution to the observed effects. Collectively, our findings demonstrate that OEA and PEA potentiate IFNβ-induced apoptosis in SH-SY5Y cells through PPARα-dependent mechanisms that synergize with, but remain9 distinct from, classical IFN signalling. This synergism promoting apoptotic cell death while modulating PD-L1 expression, highlights a novel interplay between lipid signalling and cytokine pathways in NB. These results open avenues for further studies aimed at evaluating OEA and PEA as adjuvants in IFN-based therapies and raise the possibility that combining bioactive lipids with immunomodulatory cytokines could improve therapeutic efficacy against NB and other IFN-sensitive malignancies.","abstract_html":"Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous bioactive lipids that act as selective agonists of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor implicated in lipid metabolism, inflammation, and cancer biology. While their anti-tumour potential has been suggested in various malignancies, their role in human neuroblastoma (NB) remains unexplored. NB, a paediatric solid tumour with poor prognosis in aggressive forms, may benefit from novel therapeutic strategies that exploit molecular vulnerabilities and enhance the efficacy of existing treatments. Type I interferons (IFNs), particularly IFNβ, are cytokines with well-characterized antiviral and anti-proliferative actions and documented capacity to trigger apoptosis in tumour cells, including NB. In this study, we investigated whether OEA and PEA could modulate IFNβ-induced responses in human SHSY5Y NB cells. Through a combination of viability assays, scratch wound healing, clonogenic assays, and western blotting, we show that OEA and PEA significantly enhance IFNβ-mediated cytotoxicity. Co-treatment with IFNβ and either lipid potentiated apoptosis, as indicated by increased cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP), together with reduced levels of survivin, a protein involved in anti-apoptotic regulation. Importantly, this effect occurred without amplifying canonical IFNβ signalling through the JAK-STAT pathway or PKR induction, suggesting a parallel and complementary apoptotic mechanism. Furthermore, OEA and PEA enhanced IFNβ-induced PD-L1 expression both in whole-cell lysates and on the plasma membrane. Pharmacological inhibition and the genetic silencing of PPARα attenuated PARP cleavage and PD-L1 upregulation, confirming the receptor’s contribution to the observed effects. Collectively, our findings demonstrate that OEA and PEA potentiate IFNβ-induced apoptosis in SH-SY5Y cells through PPARα-dependent mechanisms that synergize with, but remain9 distinct from, classical IFN signalling. This synergism promoting apoptotic cell death while modulating PD-L1 expression, highlights a novel interplay between lipid signalling and cytokine pathways in NB. These results open avenues for further studies aimed at evaluating OEA and PEA as adjuvants in IFN-based therapies and raise the possibility that combining bioactive lipids with immunomodulatory cytokines could improve therapeutic efficacy against NB and other IFN-sensitive malignancies.","abstract_has_math":false,"creators":["BALLA, JIHANE"],"institution":"Università degli Studi di Cagliari","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["DEDONI, SIMONA","FADDA, PAOLA"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026-02-13T00:00:00+01:00","date_published":"2026-02-13T00:00:00+01:00","updated_at":"2026-07-24T01:29:55Z","subjects":["Settore BIOS-11/A - Farmacologia"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/11584/474587","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["DEDONI, SIMONA","FADDA, PAOLA"]},{"key":"dc:creator","label":"Author","values":["BALLA, JIHANE"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2026-02-13T00:00:00+01:00"]},{"key":"dc:publisher","label":"Institution","values":["Università degli Studi di Cagliari"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Settore BIOS-11/A - Farmacologia"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/11584/474587"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous bioactive lipids that act as selective agonists of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor implicated in lipid metabolism, inflammation, and cancer biology. While their anti-tumour potential has been suggested in various malignancies, their role in human neuroblastoma (NB) remains unexplored. NB, a paediatric solid tumour with poor prognosis in aggressive forms, may benefit from novel therapeutic strategies that exploit molecular vulnerabilities and enhance the efficacy of existing treatments. Type I interferons (IFNs), particularly IFNβ, are cytokines with well-characterized antiviral and anti-proliferative actions and documented capacity to trigger apoptosis in tumour cells, including NB. In this study, we investigated whether OEA and PEA could modulate IFNβ-induced responses in human SHSY5Y NB cells. Through a combination of viability assays, scratch wound healing, clonogenic assays, and western blotting, we show that OEA and PEA significantly enhance IFNβ-mediated cytotoxicity. Co-treatment with IFNβ and either lipid potentiated apoptosis, as indicated by increased cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP), together with reduced levels of survivin, a protein involved in anti-apoptotic regulation. Importantly, this effect occurred without amplifying canonical IFNβ signalling through the JAK-STAT pathway or PKR induction, suggesting a parallel and complementary apoptotic mechanism. Furthermore, OEA and PEA enhanced IFNβ-induced PD-L1 expression both in whole-cell lysates and on the plasma membrane. Pharmacological inhibition and the genetic silencing of PPARα attenuated PARP cleavage and PD-L1 upregulation, confirming the receptor’s contribution to the observed effects. Collectively, our findings demonstrate that OEA and PEA potentiate IFNβ-induced apoptosis in SH-SY5Y cells through PPARα-dependent mechanisms that synergize with, but remain9 distinct from, classical IFN signalling. This synergism promoting apoptotic cell death while modulating PD-L1 expression, highlights a novel interplay between lipid signalling and cytokine pathways in NB. These results open avenues for further studies aimed at evaluating OEA and PEA as adjuvants in IFN-based therapies and raise the possibility that combining bioactive lipids with immunomodulatory cytokines could improve therapeutic efficacy against NB and other IFN-sensitive malignancies."]},{"key":"dc:title","label":"Title","values":["Oleoylethanolamide and palmitoylethanolamide synergize with IFNβ to potentiate apoptosis and PD-L1 induction in SH-SY5Y neuroblastoma cells"]}]}],"canonical_facts":{"dc:contributor":["DEDONI, SIMONA","FADDA, PAOLA"],"dc:creator":["BALLA, JIHANE"],"dc:date":["2026-02-13T00:00:00+01:00"],"dc:description":["Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous bioactive lipids that act as selective agonists of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor implicated in lipid metabolism, inflammation, and cancer biology. While their anti-tumour potential has been suggested in various malignancies, their role in human neuroblastoma (NB) remains unexplored. NB, a paediatric solid tumour with poor prognosis in aggressive forms, may benefit from novel therapeutic strategies that exploit molecular vulnerabilities and enhance the efficacy of existing treatments. Type I interferons (IFNs), particularly IFNβ, are cytokines with well-characterized antiviral and anti-proliferative actions and documented capacity to trigger apoptosis in tumour cells, including NB. In this study, we investigated whether OEA and PEA could modulate IFNβ-induced responses in human SHSY5Y NB cells. Through a combination of viability assays, scratch wound healing, clonogenic assays, and western blotting, we show that OEA and PEA significantly enhance IFNβ-mediated cytotoxicity. Co-treatment with IFNβ and either lipid potentiated apoptosis, as indicated by increased cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP), together with reduced levels of survivin, a protein involved in anti-apoptotic regulation. Importantly, this effect occurred without amplifying canonical IFNβ signalling through the JAK-STAT pathway or PKR induction, suggesting a parallel and complementary apoptotic mechanism. Furthermore, OEA and PEA enhanced IFNβ-induced PD-L1 expression both in whole-cell lysates and on the plasma membrane. Pharmacological inhibition and the genetic silencing of PPARα attenuated PARP cleavage and PD-L1 upregulation, confirming the receptor’s contribution to the observed effects. Collectively, our findings demonstrate that OEA and PEA potentiate IFNβ-induced apoptosis in SH-SY5Y cells through PPARα-dependent mechanisms that synergize with, but remain9 distinct from, classical IFN signalling. This synergism promoting apoptotic cell death while modulating PD-L1 expression, highlights a novel interplay between lipid signalling and cytokine pathways in NB. These results open avenues for further studies aimed at evaluating OEA and PEA as adjuvants in IFN-based therapies and raise the possibility that combining bioactive lipids with immunomodulatory cytokines could improve therapeutic efficacy against NB and other IFN-sensitive malignancies."],"dc:identifier":["https://hdl.handle.net/11584/474587"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Cagliari"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:subject":["Settore BIOS-11/A - Farmacologia"],"dc:title":["Oleoylethanolamide and palmitoylethanolamide synergize with IFNβ to potentiate apoptosis and PD-L1 induction in SH-SY5Y neuroblastoma cells"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-24T01:29:55Z"}