Nuclear medicine

This study is aim to investigate the relationship between IDH3a expression and tumor glucose uptake. Sixty‐five patients who underwent 2‐[18F]‐2‐deoxy‐D‐glucose ([18F]‐FDG) positron emission tomography/computed tomography (PET/CT) imaging before surgery and pathologically diagnosed as lung adenocarcinoma were included. All patients were divided into high (n = 31) and low (n = 34) groups according IDH3a expression by immuno histochemistry.

PET/CT imaging before surgery

Comparatively higher [18F]‐FDG uptake is find in high IDH3a expression group. Glucose transporter 1 (GLUT1) level was demonstrate to correlate with IDH3a expression, but not for hexokinase 2 (HK2). Furthermore, A549 and H1299 cells experiment showed, the expression of p‐AKT and GLUT1 were significantly downregulate after IDH3a interference. The cellular uptake of [18F]‐FDG and lactate production are significantly reduce in treatment group.

In summary, high expression of IDH3a in lung adenocarcinoma patients is associate with higher glucose uptake. IDH3a targets AKT‐GLUT1 pathway to affect glucose uptake and metabolites in lung adenocarcinoma. Repro gramming of glucose metabolism mainly refers to the generation of adenosine triphosphate (ATP); by glucose oxidative phosphorylation changing into aerobic glycolysis; which is a characteristic change of most malignant tumors.

Lung adenocarcinoma patients

Conversely, abnormal glucose metabolism (such as mutations in key enzyme genes) can also lead to malignant tumors. Isocitrate dehydrogenase (IDH) is the rate‐limiting enzyme in the Krebs cycle that catalyzes oxidative decarboxylation of isocitrate to α‐ketoglutaric acid. IDH3 is one of three subtypes of IDH, and its α subunit is a catalytic subunit having oxidative dehydrogenation activity. Recent studies have found that IDH3a mediates the aerobic glycolysis of tumor cells by upregulating hypoxia‐inducible factors (HIF); and shows that lung or breast cancer patients with high IDH3a expression have a poor prognosis.

IDH3a has also been find highly express in aflatoxin‐induce hepatocellular carcinoma and glioblastoma. However, another study find that IDH3a expression is downregulat in cancer‐associated fibroblasts, providing metabolites for the growth of tumors via aerobic glycolysis. In any case, the studies above confirm that abnormal expression of IDH3a led to reduction of α‐ketoglutarate, and it was conclude that IDH3a play a key role in tumor aerobic glycolysis.

Cancer‐associated fibroblasts

Positron emission tomography with 2‐deoxy‐2‐[fluorine‐18]fluoro‐ D‐glucose integrated with computed tomography (18F‐FDG PET/CT) is a powerful imaging tool for the detection of various cancers, providing valuable functional information based on the increased glucose uptake and glycolysis of cancer cells. The main mechanisms of [18F]‐FDG uptake is involve with increase expression of glucose transporters of cell membrane and rate‐limiting glycolytic enzymes, such as glucose transporters 1 (GLUT1) and hexokinase 2 (HK2). AKT is know as “Warburg kinase,” which promotes tumor cells metabolic reprogramming and increases cell invasiveness.