Mitochondrial dynamics in geftinib-resistant lung adenocarcinoma cells
Atsuko Kasahara1, Masafumi Noguchi2, Keitaro Shibata2, Susumu Kohno3, Chiaki Takahashi1, Noriko Gotoh1, Takashi Kohno4, Luca Scorrano5, Atsushi Hirao3 1Institute for Frontier Science Initiative, Cancer Research Institute, Kanazawa University, Japan, 2Department of Biology, University of Padua, Italy, 3Cancer Research Institute, Kanazawa University, Japan, 4National Cancer Center Research Institute, Japan, 5Department of Biology, University of Padua, Venetian Institute of Molecular Medicine, Italy
Mitochondrial pleiotropic functions, such as huge energy production, controlling metabolic pathways, apoptosis, and calcium homeostasis, are reflected by their extremely dynamic morphology, and distribution in the cells. Dynamin-like GTPase optic atrophy 1 (OPA1), mitofusin (MFN) 1, 2 fuse, and cytosolic dynamin- related protein 1 (DRP1) divides mitochondria. Fragmented mitochondria due to Drp1 up-regulation observed in high metastatic breast cancer cells (Oncogene 2013), and stem-like populations of glioma (Nat Neurosci 2015, EMBO J 2017), maintain their each malignant phenotypes. However, little is known about whether and how mitochondrial dynamics involves in drug resistance of tumour cells. Lung cancer causes terrible five-year survival rate, thus is one of the “deadly diseases” worldwide. Gefitinib specifically targeting epidermal growth factor receptor (EGFR) are developed for non-small-cell lung cancer (NSCLC). However, drug resistant cancer cells often emerge, and are able to cause tumour recurrence. Here we use gefitinib-resistant lung adenocarcinoma PC9M2 cells, which were established from gefitinib-sensitive PC9 cells in order to understand the role of mitochondrial dynamics in gaining and maintaining the gefitinib-resistance in lung adenocarcinoma cells. Mitochondria appear elongated in PC9M2 comparing to PC9, with Drp1 down-regulation. Enhanced mitochondrial respiration, and resistance to apoptotic cell death with Opa1 accumulation were observed in PC9M2. Since Wnt/β-catenin signalling is enhanced in PC9M2, a Wnt/β-catenin inhibitor, ICG001, shortens elongated mitochondria, and down-regulation of Opa1 increase β-catenin level in PC9M2, suggesting there could be an interaction between mitochondrial dynamics and Wnt/β-catenin signalling in lung adenocarcinoma cells.
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