Thermogenic protein UCP1 and UCP3 expression in nonsmall cell lung cancer: relation with glycolysis and anaerobic metabolism

Alexandra Giatromanolaki, Konstantina Balaska, Dimitra Kalamida, Christos Kakouratos, Efthimios Sivridis, Michael I. Koukourakis


Uncoupling protein 1 (UCP1) is a proton transporter/channel residing on the inner mitochondrial membrane and is involved incellular heat production. Using immunohistochemistry, we investigated the expression of UCP1 and UCP3 in a series of 98patients with non-small cell lung cancer (NSCLC) treated with surgery. Expression patterns were correlated with histopathologicalvariables, prognosis, and the expression of enzymes/proteins related to cell metabolism. Bronchial epithelium did not expressUCP1 or UCP3, while alveolar cells strongly expressed UCP1. In tumors, strong expression of UCP1 and UCP3 was recorded in43/98 (43.8%) and 27/98 (27.6%) cases, respectively. UCP1 was significantly associated with squamous cell histology (P = 0.05),whilst UCP3 was more frequently overexpressed in large cell carcinomas (P = 0.08), and was inversely related to necrosis (P =0.009). In linear regression analysis, UCP1 was directly related to markers of glycolysis [hexokinase (HXKII) andphosphofructokinase (PFK1)] and anaerobic glucose metabolism [pyruvate dehydrogenase kinase (PDK1) and lactatedehydrogenase (LDH5)]. UCP3 was directly linked with a glucose transporter (GLUT2), monocarboxylate transporter (MCT2),glycolysis markers (PFK1 and aldolase), and with the phosphorylation of pyruvate dehydrogenase (pPDH). Kaplan-Meier survivalanalysis showed that UCP3 was significantly related to poor prognosis in squamous cell carcinomas (P = 0.04). UCP1 and UCP3are overexpressed in a large subgroup of non-small cell lung tumors and their expression coincides with increased glucoseabsorption, intensified glycolysis, and anaerobic glucose usage. Whether UCPs are targets for therapeutic interventions in lungcancer is a hypothesis that demands further investigation.


Lung cancer; thermogenesis; UCP1; UCP3; glycolysis; anaerobic metabolism

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