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Article: Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer

TitleOxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer
Authors
Issue Date2016
Citation
Cell Death and Differentiation, 2016, v. 23, n. 9, p. 1542-1554 How to Cite?
AbstractTumour 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.
Persistent Identifierhttp://hdl.handle.net/10722/341185
ISSN
2023 Impact Factor: 13.7
2023 SCImago Journal Rankings: 4.102
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMatassa, D. S.-
dc.contributor.authorAmoroso, M. R.-
dc.contributor.authorLu, H.-
dc.contributor.authorAvolio, R.-
dc.contributor.authorArzeni, D.-
dc.contributor.authorProcaccini, C.-
dc.contributor.authorFaicchia, D.-
dc.contributor.authorMaddalena, F.-
dc.contributor.authorSimeon, V.-
dc.contributor.authorAgliarulo, I.-
dc.contributor.authorZanini, E.-
dc.contributor.authorMazzoccoli, C.-
dc.contributor.authorRecchi, C.-
dc.contributor.authorStronach, E.-
dc.contributor.authorMarone, G.-
dc.contributor.authorGabra, H.-
dc.contributor.authorMatarese, G.-
dc.contributor.authorLandriscina, M.-
dc.contributor.authorEsposito, F.-
dc.date.accessioned2024-03-13T08:40:50Z-
dc.date.available2024-03-13T08:40:50Z-
dc.date.issued2016-
dc.identifier.citationCell Death and Differentiation, 2016, v. 23, n. 9, p. 1542-1554-
dc.identifier.issn1350-9047-
dc.identifier.urihttp://hdl.handle.net/10722/341185-
dc.description.abstractTumour 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.-
dc.languageeng-
dc.relation.ispartofCell Death and Differentiation-
dc.titleOxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/cdd.2016.39-
dc.identifier.pmid27206315-
dc.identifier.scopuseid_2-s2.0-84969730632-
dc.identifier.volume23-
dc.identifier.issue9-
dc.identifier.spage1542-
dc.identifier.epage1554-
dc.identifier.eissn1476-5403-
dc.identifier.isiWOS:000381072800011-

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