Abstract
BackgroundAlterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer. Despite an extensive characterization of each of them separately, the links between EMT and glucose metabolism of tumor cells remain elusive. Here we show that the neuronal glucose transporter GLUT3 contributes to glucose uptake and proliferation of lung tumor cells that have undergone an EMT.ResultsUsing a panel of human non-small cell lung cancer (NSCLC) cell lines, we demonstrate that GLUT3 is strongly expressed in mesenchymal, but not epithelial cells, a finding corroborated in hepatoma cells. Furthermore, we identify that ZEB1 binds to the GLUT3 gene to activate transcription. Importantly, inhibiting GLUT3 expression reduces glucose import and the proliferation of mesenchymal lung tumor cells, whereas ectopic expression in epithelial cells sustains proliferation in low glucose. Using a large microarray data collection of human NSCLCs, we determine that GLUT3 expression correlates with EMT markers and is prognostic of poor overall survival.ConclusionsAltogether, our results reveal that GLUT3 is a transcriptional target of ZEB1 and that this glucose transporter plays an important role in lung cancer, when tumor cells loose their epithelial characteristics to become more invasive. Moreover, these findings emphasize the development of GLUT3 inhibitory drugs as a targeted therapy for the treatment of patients with poorly differentiated tumors.
Highlights
Alterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer
We discovered a strong association between the EMT program and the induction of the glucose transporter GLUT3 in non-small cell lung cancer (NSCLC) and extended this observation to tumor cells from another cancer type, hepatocellular carcinoma (HCC)
GLUT3 expression correlates with EMT To determine if the neuronal glucose transporter GLUT3 is expressed in lung tumor cells, we used a panel of ten human NSCLC cell lines
Summary
Alterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer. Despite an extensive characterization of each of them separately, the links between EMT and glucose metabolism of tumor cells remain elusive. We show that the neuronal glucose transporter GLUT3 contributes to glucose uptake and proliferation of lung tumor cells that have undergone an EMT. In order to build the necessary biomass required for proliferation, tumor cells increase their glucose consumption [2]. Glucose transporters of the GLUT (SLC2A) family are at the first step of cellular glucose utilization, mediating glucose entry by facilitative diffusion. The GLUT family is composed of 14 members that transport glucose or other substrates in different tissues, with different efficiencies [3].
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