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Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells

2017; Impact Journals LLC; Volume: 8; Issue: 55 Linguagem: Inglês

10.18632/oncotarget.21885

1949-2553

Fintan Geoghegan, Robert Buckland, Eric T. Rogers, Karima Khalifa, Emma B. O’Connor, Mary F. Rooney, Parviz Behnam‐Motlagh, Torbjörn Nilsson, Kjell Grankvist, Richard K. Porter,

Autophagy in Disease and Therapy

// Fintan Geoghegan 1 , Robert J. Buckland 2 , Eric T. Rogers 1 , Karima Khalifa 1 , Emma B. O'Connor 1 , Mary F. Rooney 1 , Parviz Behnam-Motlagh 2 , Torbjörn K. Nilsson 2 , Kjell Grankvist 2 and Richard K. Porter 1 1 School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, Dublin 2, Ireland 2 Dept of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Correspondence to: Robert J. Buckland, email: robert.buckland@umu.se Keywords: cisplatin resistance, bioenergetics, SIRT3, non-small cell lung cancer, mesothelioma Abbreviations: OCR: oxygen consumption rate; ECAR: extracellular acidification rate Received: July 22, 2017 Accepted: September 21, 2017 Published: October 16, 2017 ABSTRACT 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-γ co-activator 1-alpha (PGC1α), 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 (HIF1α) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit α2 (AMPKα2) 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-1α stabilization.