title: Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.
abstract: Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: D S
authors.initials: DS
authors.lastname: Matassa
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Amoroso
authors.affiliation: Imperial College London, Ovarian Cancer Action Research Centre, Department of Cancer and Surgery, Institute of Reproductive and Developmental Biology, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Avolio
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Arzeni
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Procaccini
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base Cliniche (CISI), Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Faicchia
authors.affiliation: Laboratorio di Ricerca Preclinica e Traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, PZ Italy.
authors.forename: F
authors.initials: F
authors.lastname: Maddalena
authors.affiliation: Laboratorio di Ricerca Preclinica e Traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, PZ Italy.
authors.forename: V
authors.initials: V
authors.lastname: Simeon
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Agliarulo
authors.affiliation: Imperial College London, Ovarian Cancer Action Research Centre, Department of Cancer and Surgery, Institute of Reproductive and Developmental Biology, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Zanini
authors.affiliation: Laboratorio di Ricerca Preclinica e Traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, PZ Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mazzoccoli
authors.affiliation: Imperial College London, Ovarian Cancer Action Research Centre, Department of Cancer and Surgery, Institute of Reproductive and Developmental Biology, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Recchi
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Stronach
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base Cliniche (CISI), Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marone
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: G
authors.identifier: 0000-0001-9429-0616
authors.initials: G
authors.lastname: Matarese
authors.affiliation: Laboratorio di Ricerca Preclinica e Traslazionale, IRCCS-CROB, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, PZ Italy.|Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Foggia, Foggia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Landriscina
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Esposito
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006019:Glycolysis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002945:Cisplatin; D018841:HSP90 Heat-Shock Proteins; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000099184:Serum-Glucocorticoid Regulated Kinases; C092306:TRAP1 protein, human