NADH dehydrogenase complex I is overexpressed in incipient metastatic murine colon cancer cells

Marquez,Joana; Kratchmarova,Irina; Akimov,Vyacheslav; Unda,Fernando; Ibarretxe,Gaskon; Clerigué,Ariane   Schaub; Osinalde,Nerea; Badiola,Iker

doi:10.3892/or.2018.6892

NADH dehydrogenase complex I is overexpressed in incipient metastatic murine colon cancer cells

Authors:
- Joana Marquez
- Irina Kratchmarova
- Vyacheslav Akimov
- Fernando Unda
- Gaskon Ibarretxe
- Ariane Schaub Clerigué
- Nerea Osinalde
- Iker Badiola
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Affiliations: Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), 48940 Leioa, Spain, Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark, CIC bioGUNE, Bizkaia Technology Park, Derio, 48160 Bizkaia, Spain, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, UPV/EHU, 01006 Vitoria‑Gasteiz, Spain
Published online on: November 27, 2018 https://doi.org/10.3892/or.2018.6892
Pages: 742-752
Copyright: © Marquez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colon cancer is one of the most frequently occurring types of cancers in the world. Primary tumours are treated very efficiently, but the metastatic cases are known to have severe outcomes. Therefore, the aim of the present study was to obtain a greater understanding of the transformation of primary colon cancer cells into metastatic phenotypes. Small changes in protein expression provoke the metastatic phenotype transformation. More sensitive methods to detect small variations are required. A murine colon cancer cell line with metastatic characteristics in a very early phase was created in order to investigate the first steps of transformation using a murine liver metastasis model. The protein expression patterns of metastatic and non‑metastatic cells were compared using the stable isotope labelling by amino acids in cell culture method in combination with mass spectrometry. Quantitative proteomics data indicated that nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase complex I was overexpressed in metastatic cells with respect to non‑metastatic cells. Since the NADH dehydrogenase complex catalyses the oxidation of NADH to NAD+, the functionality of the complex was studied by measuring the amount of NADH. The results revealed that metastatic cells accumulate more NADH and reactive oxygen species. In addition, the mitochondrial membrane potential of metastatic cells was lower than that of non‑metastatic cells, indicating that the activity of NADH dehydrogenase and the mitochondrial oxidative chain were decreased in metastatic cells. During the incipient transformation of primary cancer cells, NADH dehydrogenase complex I was overexpressed but then became inactive due to the Warburg effect, which inhibits mitochondrial activity. In the first step of transformation, the high energy demand required in an adverse environment is fulfilled by overexpressing components of the respiratory chain, a fact that should be considered for future anti‑metastatic therapies.

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