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

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.

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

“…This thrombolytic response was independent of changes in arterial blood pressure; instead, the effects of MNA were mediated via an increase in cyclooxygenase-2 (COX-2)-mediated release of prostacyclin (PGI 2 ). MNA reduced apoptosis of SH-SY5Y human neuroblastoma cells in a dose-dependent manner [37], in addition to replicating many of the effects of NNMT expression upon tumour-promoting biochemical changes such as increased ATP synthesis and CxI activity, plus changes in cell morphology [37,108], all cognisant with changes observed during metastasis in cancers such as colorectal carcinoma [146][147][148] and breast cancer [149]. Elevated MNA levels correlate with lower survival rate and shorter life expectancy of patients with cervical cancer and thus most likely contributes to the disease progression [150].…”

Role of tyrosine phosphorylation in modulating cancer cell metabolism

“…In cancer cells, these Complex I-related events support cell proliferation, resistance to cell death, and promotion of metastasis [106]. Complex I has been found overexpressed in different types of cancer including metastatic colon carcinoma [107]. However, overexpression of Complex I could result in an excessive ROS production, with the consequent risk of inducing severe cell damage and impairing cell proliferation.…”

Identification of an m6A-Related Long Noncoding RNA Risk Model for Predicting Prognosis and Directing Treatments in Patients With Colon Adenocarcinoma

“…Focal adhesion plays a key role in tumor invasiveness and metastasis, drug resistance, and radioresistance ( Eke and Cordes, 2015 ). The NADH dehydrogenase complex has been reported to be overexpressed in metastatic mouse colon tumor cells ( Marquez et al, 2019 ). In conclusion, functional analysis provided new insights into the process and mechanism of m6A-lncRNAs in COAD.…”