Regulation of the Warburg Effect in Early-Passage Breast Cancer Cells

Abstract

Malignancy in cancer is associated with aerobic glycolysis (Warburg effect) evidenced by increased trapping of [(18)F]deoxyglucose (FdG) in patients imaged by positron emission tomography (PET). [(18)F]deoxyglucose uptake correlates with glucose transporter (GLUT-1) expression, which can be regulated by hypoxia-inducible factor 1 alpha (HIF-1alpha). We have previously reported in established breast lines that HIF-1alpha levels in the presence of oxygen leads to the Warburg effect. However, glycolysis and GLUT-1 can also be induced independent of HIF-1alpha by other factors, such as c-Myc and phosphorylated Akt (pAkt). This study investigates HIF-1alpha, c-Myc, pAkt, and aerobic glycolysis in low-passage breast cancer cells under the assumption that these represent the in vivo condition better than established lines. Similar to in vivo FdG-PET or primary breast cancers, rates of glycolysis were diverse, being higher in cells expressing both c-Myc and HIF-1alpha and lower in cell lines low or negative in both transcription factors. No correlations were observed between glycolytic rates and pAkt levels. Two of 12 cell lines formed xenografts in mice. Both were positive for HIF-1alpha and phosphorylated c-Myc, and only one was positive for pAkt. Glycolysis was affected by pharmacological regulation of c-Myc and HIF-1alpha. These findings suggest that c-Myc and/or HIF-1alpha activities are both involved in the regulation of glycolysis in breast cancers.

Regulation of glucose transporter protein-1 and vascular endothelial growth factor by hypoxia inducible factor 1α under hypoxic conditions in Hep-2 human cells

“…This then combines with the promoter and enhancer on Glut-1 mRNA, leading to Glut-1 transcription to maintain the metabolism of tumor cells and supply them with a material foundation for further growth and metastasis. Glut-1 is mainly regulated by HIF-1α; however, it is also affected by other regulators (10).…”

PET Imaging of Glutaminolysis in Tumors by 18F-(2S,4R)4-Fluoroglutamine

“…Every year, millions of 18 F-FDG scans are conducted within the United States. Despite the tremendous promise and use of 18 F-FDG PET, a noticeable portion of these tumors, which are 18 F-FDG PET-negative, go undetected (6), possibly suggesting that some types of tumors are switching their metabolism and energy consumption from glucose to other nutrients, such as glutamine. Glutamine has the highest concentration (0.5-1 mM) among all of the amino acids circulating in the blood.…”

Preparation and Characterization of l-[5-11C]-Glutamine for Metabolic Imaging of Tumors

“…This is the biochemical basis of using 18 F-FDG PET as a diagnostic tool for the detection of human cancers (9,10). Despite the utility of 18 F-FDG PET for staging and monitoring of cancer in humans, there is a growing realization that up to 30% of actively growing cancers are 18 F-FDG-negative and cannot be detected by 18 F-FDG PET (11). The observation strongly suggests that tumor cells may have alternative nutrient and metabolic strategies for survival and that glucose may not be the only source of energy and metabolic substrates for tumor growth (Fig.…”

“…But, it is likely that using L-[5-11 C]-glutamine PET to study glutaminolysis might measure the additive effects of upregulation of glu-tamine transport and glutamine use. Similar to the tumor cell trapping of 18 F-FDG through upregulation of membranebound glucose transporter 1 and cytosol hexokinase, glutamine may be used via the glutamine transporter (ASCT2) and glutaminases located in the cytosol (9,11,18). Previously, 13 N-glutamine imaging of various spontaneous canine tumors showed that the imaging agent displayed a positive correlation with postmortem findings (20).…”