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

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Title: Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer
Authors: Matassa, DS
Amoroso, MR
Lu, H
Avolio, R
Arzeni, D
Procaccini, C
Faicchia, D
Maddalena, F
Simeon, V
Agliarulo, I
Zanini, E
Mazzoccoli, C
Recchi, C
Stronach, E
Marone, G
Gabra, H
Matarese, G
Landriscina, M
Esposito, F
Item Type: Journal Article
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.Cell Death and Differentiation advance online publication, 20 May 2016; doi:10.1038/cdd.2016.39.
Issue Date: 20-May-2016
Date of Acceptance: 21-Mar-2016
URI: http://hdl.handle.net/10044/1/34624
DOI: https://dx.doi.org/10.1038/cdd.2016.39
ISSN: 1476-5403
Publisher: Nature Publishing Group
Start Page: 1542
End Page: 1554
Journal / Book Title: Cell Death and Differentiation
Volume: 23
Copyright Statement: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Keywords: Biochemistry & Molecular Biology
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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