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. 2008 Aug;10(8):745-56.
doi: 10.1593/neo.07724.

Regulation of the Warburg effect in early-passage breast cancer cells

Ian F Robey  1 , Renu M Stephen, Kathy S Brown, Brenda K Baggett, Robert A Gatenby, Robert J Gillies
Affiliations

Regulation of the Warburg effect in early-passage breast cancer cells

Ian F Robey et al. Neoplasia. 2008 Aug.

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.

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Figures

Figure 1
Figure 1
Corelationships between glycolytic markers in breast tumor lines. Linear correlations in the 12 primary breast tumor lines between LPRs and GURs (P = .0173; A), GURs and GLUT-1 mRNA levels (B), GUR and GLUT-3 mRNA levels (C), LPRs and GLUT-1 mRNA levels (D), and lactate production and GLUT-3 mRNA (E).
Figure 2
Figure 2
Nuclear expression of phosphorylated c-Myc and HIF-1α. Immunoblot analysis of c-MycThr58/Ser62, total c-Myc, HIF-1α, and lamin loading from nuclear extracts of ACC-cell lines (A). These data were correlated to activities, as measured by ELISA (B, D) and LPR (C, E).
Figure 3
Figure 3
Nuclear expression of HIF-2α. Immunoblot analysis of HIF-2α and lamin loading from nuclear extracts of ACC-812 and ACC-893.
Figure 4
Figure 4
Nuclear expression of pAkt and total Akt. (A) Immunoblot of Ser473 pAkt, total Akt, and GAPDH control from nuclear extracts of ACC breast tumor lines. (B) Correlation of pAkt mean band intensities normalized to total Akt expression and lactate production, P = .87.
Figure 5
Figure 5
Expression of phosphorylated c-Myc, HIF-1α, and lactate production in TPA-treated breast tumor cell line. Increase of c-Myc expression and lactate production when ACC-3199 cells are treated with 15 mM TPA for 2 hours.
Figure 6
Figure 6
Effect of PX-478 on HIF-1α and glycolysis. Dose-dependent decrease in glucose uptake in MDA-mb-231 cells (20 and 40 µg/ml) after 24 hours of treatment with PX-478 under hypoxia (O2 = 2%). *P = .01 compared to untreated controls.
Figure 7
Figure 7
Immunohistochemistry for pAkt in ACC-3171 and ACC-3199 tumors. Breast tumor cell lines grown in SCID mice and then reimplanted into new SCID mice were stained for pAkt. ACC-3171 demonstrated a positive staining for pAkt, whereas ACC-3199 was negative for pAkt.
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