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Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 55, p. 94711-94725Article in journal (Refereed) Published
Abstract [en]

Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC , 2017. Vol. 8, no 55, p. 94711-94725
Keywords [en]
cisplatin resistance, bioenergetics, SIRT3, non-small cell lung cancer, mesothelioma
National Category
Cell Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-142242DOI: 10.18632/oncotarget.21885ISI: 000414608400121OAI: oai:DiVA.org:umu-142242DiVA, id: diva2:1164556
Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2018-06-09Bibliographically approved

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Buckland, Robert J.Behnam-Motlagh, ParvizNilsson, Torbjörn K.Grankvist, Kjell

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