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

Abstract

Uncoupling protein 1 (UCP1) is a proton transporter/channel residing on the inner mitochondrial membrane and is involved in cellular heat production. Using immunohistochemistry, we investigated the expression of UCP1 and UCP3 in a series of 98 patients with non-small cell lung cancer (NSCLC) treated with surgery. Expression patterns were correlated with histopathological variables, prognosis, and the expression of enzymes/proteins related to cell metabolism. Bronchial epithelium did not express UCP1 or UCP3, while alveolar cells strongly expressed UCP1. In tumors, strong expression of UCP1 and UCP3 was recorded in 43/98 (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) and phosphofructokinase (PFK1)] and anaerobic glucose metabolism [pyruvate dehydrogenase kinase (PDK1) and lactate dehydrogenase (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 survival analysis showed that UCP3 was significantly related to poor prognosis in squamous cell carcinomas (P = 0.04). UCP1 and UCP3 are overexpressed in a large subgroup of non-small cell lung tumors and their expression coincides with increased glucose absorption, intensified glycolysis, and anaerobic glucose usage. Whether UCPs are targets for therapeutic interventions in lung cancer is a hypothesis that demands further investigation.

Identification of UCP1 and UCP2 as Potential Prognostic Markers in Breast Cancer: A Study Based on Immunohistochemical Analysis and Bioinformatics

“…UCPs are potential prognostic markers in several types of malignancies, including BC, however, their precise role remains debatable ( Ayyasamy et al, 2011a ; Li et al, 2013 ; Pitt, 2015 ; Giatromanolaki et al, 2017a ; Oleksiewicz et al, 2017 ). Evidence shows that UCP1 has both malignancy-promoting and -suppressing effects.…”

“…UCP2 also has a paradoxical role in tumor progression. It contributes to tumor progression by promoting metabolism, regulating ROS, preventing tumor apoptosis, and promoting tumor resistance to chemotherapy ( Ayyasamy et al, 2011b ; Brandi et al, 2016 ; Giatromanolaki et al, 2017b ; Yu et al, 2020 ). However, evidence also suggests that overexpression of UCP2 does not affect ROS production, but decreases glycolytic activity in cancer cells ( Esteves et al, 2014 ).…”

“…To date, five UCPs (UCP1–UCP5) have been identified in mammals ( Echtay et al, 2018 ). Among them, UCP1 and UCP2 are associated with multiple malignant tumors, including colon cancer, non-small cell lung cancer, pancreatic cancer, and BC ( Ayyasamy et al, 2011a ; Li et al, 2013 ; Pitt, 2015 ; Giatromanolaki et al, 2017a ; Oleksiewicz et al, 2017 ). Currently, there are different conclusions on the role of UCPs in malignancy.…”

“…Currently, there are different conclusions on the role of UCPs in malignancy. Some studies suggest that UCPs (mainly UCP2) accelerate tumor progression by promoting aerobic glycolysis (Warburg effect) and inhibiting reactive oxygen species (ROS), thereby enhancing the resistance of cancer cells against chemotherapeutic agents ( Ayyasamy et al, 2011b ; Brandi et al, 2016 ; Giatromanolaki et al, 2017b ; Yu et al, 2020 ). However, UCP1 reportedly can inhibit tumor progression by initiating autophagy and lipid browning programs ( Xiao et al, 2019 ), along with snail-mediated repression of fructose-bisphosphatase 1 (FBP1) ( Zhang et al, 2021 ).…”

Heterogeneity of Glucose Transport in Lung Cancer

“…Its kinetics with low affinity is adapted for glucose and fructose export and sensing, rather than uptake in epithelial cells. Its expression has been reported in breast, colon, liver, and lung cancer [ 188 , 189 , 190 ]. GLUT4 is the insulin-regulated member of the family [ 125 , 126 ], expressed in the following insulin-responsive tissues: skeletal muscle, adipose tissue, and heart [ 122 ].…”