Kruppel-like factor 2 disturb non-small cell lung cancer energy metabolism by inhibited glutamine consumption

Non–small cell lung cancer accounts for 85% of all types of lung cancer and is the leading cause of worldwide cancer-associated mortalities. MiR-124 is epigenetically silenced in various types of cancer and plays important roles in tumor development and progression. MiR-124 was also significantly downregulated in non–small cell lung cancer patients. Glycolysis has been considered as a feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key enzymes in the regulation of glycolysis and energy metabolism in cancer cells. However, the role of miR-124 in non–small cell lung cancer cell proliferation, glycolysis, and energy metabolism remains unknown. In this research, cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore, glucose consumption and lactic acid production were assessed; adenosine triphosphate content and NAD+/NADH were also detected. These tests were conducted using the normal non–small cell lung cancer cell line A549, which was transfected variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1, and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly decreased cell growth, glucose consumption, lactate production, and energy metabolism. MiR-124 also negatively regulates glycolysis rate–limiting enzymes, glucose transporter 1 and hexokinase II. Our results also showed that miR-124 negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of miR-124 on cell proliferation and glycolytic metabolism in non–small cell lung cancer. AKT inhibition blocks miR-124 silencing–induced AKT1/2, glucose transporter 1, hexokinase II activation, cell proliferation, and glycolytic or energy metabolism changes. In summary, this study demonstrated that miR-124 is able to inhibit proliferation, glycolysis, and energy metabolism, potentially by targeting AKT1/2–glucose transporter 1/hexokinase II in non–small cell lung cancer cells.

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Lean Body Mass and Endocrine Status But Not Age Are Determinants of Resting Energy Expenditure in Patients with Non-Small Cell Lung Cancer

Annals of Nutrition and Metabolism ◽

10.1159/000504874 ◽

2019 ◽

Vol 75 (4) ◽

pp. 223-230

Author(s):

Guillaume Ulmann ◽

Anne Jouinot ◽

Camille Tlemsani ◽

Emmanuel Curis ◽

Isabelle Kousignian ◽

...

Keyword(s):

Lung Cancer ◽

Energy Metabolism ◽

Energy Expenditure ◽

Small Cell Lung Cancer ◽

Lean Body Mass ◽

Cell Lung Cancer ◽

Resting Energy Expenditure ◽

Small Cell ◽

Small Cell Lung ◽

Impaired Energy Metabolism

Background: Cancer and aging are both frequently associated with malnutrition, a factor of poor prognosis. In adult cancer patients, this may be related in part to impaired energy metabolism, with higher than predicted resting energy expenditure (REE) in about 50% of patients. We hypothesized that frequently impaired energy metabolism in elderly patients could potentiate cancer-associated hypermetabolism, further promoting risk of malnutrition. Objective: To study the hypermetabolic response to cancer in a predominantly aged population and the potential underlying determinants. Methods: This was a cross-sectional exploratory study in patients with non-small-cell lung cancer. REE was measured by indirect calorimetry. Body composition was determined from a single CT scan imaging at L3 level. Endocrine, inflammatory, nutritional and metabolic status were evaluated. Results: Twenty-seven patients, of median age 68 years (range 32–81) completed the study. In this population, mean measured REE was 7.5% higher than calculated REE. Sex and weight accounted for about 51% of REE variations, whereas age accounted only for 4%. However, these parameters did not explain the REE-to-lean body mass (LBM) ratio variations, suggesting that they influenced REE only through their effect on LBM. Among the other parameters evaluated, only the thyroid-stimulating hormone and interleukin-6 plasma levels appeared to have an influence on REE. The study of the consequences of this increase in REE-to-LBM ratio showed a growing inability of patients to meet their energy needs but showed no effect on nutritional markers such as transthyretin. Conclusions: The results of this pilot study suggest that in our population, age was not an important factor of REE. The elevated energy metabolism was associated with patients’ failure to increase their energy intakes sufficiently, which can contribute to the development of cachexia. Clinical Trial: This trial is registered at clinicaltrials.gov under NCT0314.

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Ring Finger Protein 180 Suppresses Cell Proliferation and Energy Metabolism of Non-Small Cell Lung Cancer Through Down-Regulating C-myc

10.21203/rs.3.rs-111371/v1 ◽

2020 ◽

Author(s):

Yi Ding ◽

Yi Lu ◽

Xinjie Xie ◽

Lei Cao ◽

Shiying Zheng

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Energy Metabolism ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Ring Finger ◽

Small Cell ◽

Ring Finger Protein ◽

Small Cell Lung ◽

Finger Protein

Abstract BackgroundNon-small cell lung cancer (NSCLC) causes a great number of cancer-related mortality worldwide, but the biomarkers for prognosis of NSCLC are scarce because of their inconsistent efficiency. Proteins containing RING finger domain are the key mediator for ubiquitination, which controls cell cycle and regulates tumor progression. Ring Finger Protein 180 (RNF180) has been reported to suppress gastric cancer, whereas its function in NSCLC is still unclear. In this study, the association between RNF180 expression and NSCLC as well as the effect of RNF180 in cellular proliferation and metabolism of NSCLC were investigated. MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to analyse RNF180 levels. Moreover, RNA interference (RNAi) and lentiviral-mediated vector transfections were performed to silence and overexpress RNF180. Further, Cell Counting Kit-8 (CCK-8) was used to assess its biological function in cell proliferation. A xenograft model was used to examine RNF180 function in vivo. ResultsWe found that the expression of RNF180 was decreased in NSCLC tissues, and its expression was positively correlated with the survival rate of NSCLC patients. Furthermore, the overexpression of RNF180 in NSCLC cells suppressed their proliferation, glycolytic activities, and mitochondrial respiration in vitro, and it restricted the tumorigenicity in mice. In addition, RNF180 knockdown promoted NSCLC cell proliferation and energy metabolism, whereas these promotive effects were counteracted by C-myc inhibitor. The underlying anti-NSCLC mechanism of RNF180 involved in the down-regulation of C-myc through ubiquitin-dependent degradation, and subsequently reduced C-myc downstream: lactate dehydrogenase-A (LDHA) and hexokinase-2 (HK2). ConclusionsThese results firstly indicated the anti-tumor properties of RNF180 and its significant correlation with NSCLC, which endorses RNF180 with the potential as efficient prognostic biomarker for tumor recurrence in NSCLC.

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