Effect of IDH3α on glucose uptake in lung adenocarcinoma

Objectives: Recent studies have found that the α catalytic subunit of IDH3 as a upstream of hypoxia inducible factors expressed highly in malignant tumors (lung cancer, breast cancer and liver cancer), which plays an important role in tumor cell metabolism reprogramming, and it could be a anti-energy metabolic therapy target potentially. However, can IDH3α highly expression affect the glucose uptake of tumor has not been investigated. The purpose of this study was to investigate the relationship between IDH3α expression and tumor glucose uptake, and the mechanism of its effects on glucose uptake in lung adenocarcinoma cells. Methods:The patients who taken ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) imaging preoperative, and were under the pathological diagnosis of lung adenocarcinoma were included, among whom 65 cases were selected finally. IDH3α, glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression in the lesions of lung adenocarcinoma patients were detected by immunohistochemical. To investigate the relationship between IDH3α expression of lung adenocarcinoma and aerobic glycolysis, the correlation between IDH3α expression and the semi-quantitative index of ¹⁸F-FDG PET/CT imaging including maximum standard uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were analyzed. Lung adenocarcinoma cell lines A549 and H1299 were selected, the IDH3α expression was silenced by siRNA. Real-time PCR was used to detect the mRNA expression of GLUT1 and HK2 after IDH3α downregulation, and Western blot was used to detect the protein expression of phosphorylated serine threonine kinase (p-AKT), GLUT1 and HK2 after IDH3α silenced; ¹⁸F-FDG uptake was detected by γ counter; Adenosine Triphosphate (ATP) production and lactic acid in the culture medium were detected after IDH3α downregulated. Results: According to the expression of IDH3α by immunohistochemical, the patients were divided into high expression group (n = 31) and low expression group (n = 34), SUVmax, MTV and TLG in the high expression group were 8.0±5.0, 5.5±5.3 and 22.1±21.2, respectively, SUVmax, MTV and TLG in the low expression group were 5.4±3.8, 3.0±2.1 and 9.3±9.1, respectively. There were significant difference between these two groups (P<0.05). The transfection efficiency by IDH3α siRNA in lung adenocarcinoma cell line A549 and H1299 was detected by Real-time PCR. The mRNA of GLUT1 was downregulated after IDH3α interferenced, the difference was statistically significant (P<0.05), but there was no obvious change in HK2; Western blot showed that protein expression of p-AKT, GLUT1 was downregulated, and the expression of HK2 protein had no obvious change; compared with normal control group, ¹⁸F-FDG uptake detection showed that uptake of ¹⁸F-FDG; Lactic acid in the culture medium reduced significantly (P<0.05), but the production of ATP did not change significantly. Conclusion: High expression of IDH3α in lung adenocarcinoma patients showed higher glucose uptake than low expression ones. IDH3α affect glucose uptake of lung cancer through AKT-GLUT1 pathway, the down-regulation of IDH3α can reduce the generation of lactic acid in tumor cells.