DNA Damage–Induced Modulation of GLUT3 Expression Is Mediated through p53-Independent Extracellular Signal-Regulated Kinase Signaling in HeLa Cells

Abstract

Many cancer cells exhibit increased rates of uptake and metabolism of glucose compared with normal cells. Glucose uptake in mammalian cells is mediated by the glucose transporter (GLUT) family. Here, we report that DNA-damaging anticancer agents such as Adriamycin and etoposide suppressed the expression of GLUT3, but not GLUT1, in HeLa cells and a tumorigenic HeLa cell hybrid. Suppression of GLUT3 expression determined by the real-time PCR was also evident with another DNA-damaging agent, camptothecin, which reduced the promoter's activity as determined with a luciferase-linked assay. The suppression by these agents seemed to be induced independently of p53, and it was evident when wild-type p53 was overproduced in these cells. In contrast, the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) kinase (MEK) inhibitor U0126 (but not the phosphoinositide 3-kinase inhibitor LY294002) prevented the drug-induced suppression as determined by reverse transcription-PCR and promoter assays. Furthermore, overexpression of GLUT3 in HeLa cell hybrids increased resistance to these drugs, whereas depletion of the gene by small interfering RNA rendered the cells more sensitive to the drugs, decreasing glucose consumption. The results suggest that DNA-damaging agents reduce GLUT3 expression in cancer cells through activation of the MEK-ERK pathway independently of p53, leading to cell death or apoptosis. The findings may contribute to the development of new chemotherapeutic drugs based on the GLUT3-dependent metabolism of glucose.

A Whole-Body Dual-Modality Radionuclide Optical Strategy for Preclinical Imaging of Metastasis and Heterogeneous Treatment Response in Different Microenvironments

“…However, no significant loss of cells due to completion of the apoptotic program could be confirmed by histology in the primary tumors at this time point after etoposide treatment. Therefore, the reduced uptake of 18 F-FDG is a direct result of etoposide affecting GLUTs and is in agreement with previous reports (10,12). Although continuous interference with glucose uptake can also kill cells because of a lack of nutrients, it is unclear over what time scale this happens and whether it leads to selection, − and 18 F-FDG, respectively).…”

“…Another complication is downmodulation of GLUTs on cancer treatment (10). For example, the genotoxic neoadjuvant etoposide, a toposiomerase II inhibitor leading to apoptosis in highly proliferating cells, negatively affects GLUT activity and expression in various cancer cell types (11,12).…”

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

“…The role of the p53 tumor suppressor gene in cancer metabolism could be summarized as promoting oxidative phosphorylation and reducing glycolysis. The effect of p53 on glycolysis mainly depends on the reduced expression of glucose transporters[66]. Recently, we investigated the role of the tumor suppressor gene Ras-related associated with diabetes (RRAD) in HCC.…”

An ataxia-telangiectasia-mutated (ATM) kinase mediated response to DNA damage down-regulates the mRNA-binding potential of THOC5

“…Thus, the inhibition of mRNA-binding potential of THOC5 may be essential to block uncontrolled differentiation. Interestingly, it has been reported that the treatment of HeLa cells with DNA damage reagents, such as adriamycin or etoposide, suppressed Glut3 (Slc2a3) mRNA expression (Watanabe et al 2010). We have previously shown that knockout of THOC5 down-regulated Glut3 mRNA more than sevenfold (Guria et al 2011), suggesting that the down-regulation of Glut3 mRNA, which was observed under conditions of DNA damage, may also be due to the loss of mRNA-binding potential of THOC5.…”