Regulation of prostate cancer cell division by glucose

Abstract

Previous studies have shown that rapid cell proliferation is associated with elevated glucose consumption. However, those studies did not establish whether glucose is required for prostate cancer cell proliferation or define the molecular mechanisms by which glucose regulates cell division. We addressed these issues by studying two metastatic human prostate cancer cell lines: DU145, which is androgen independent and highly proliferative; and LNCaP, which is androgen dependent and relatively slow growing. We found that proliferation of DU145 cells was significantly inhibited by reduction of glucose in the medium to 0.5 g/L, which is half the physiologic concentration, whereas LNCaP cells grew at control rates even in the presence of only 0.05 g/L glucose. Glucose deprivation of DU145 cells caused a 90% reduction in DNA synthesis; a 10-20-fold reduction in cyclins D and E and CDK4 levels; and cell cycle arrest in G0-G1. However, glucose deprivation did not cause global inhibition of protein synthesis, since mutant p53 levels increased in glucose-deprived DU145 cells. This observed increase in mutant p53 levels was not associated with a rise in p21 levels. Glucose deprivation of DU145 cells also led to apparent dephosphorylation of mutant retinoblastoma (RB) protein. We conclude that: 1) high levels of glucose consumption are required for rapid proliferation of androgen-independent prostate cancer cells, 2) glucose may not be required for slow growth of androgen-dependent prostate cancer cells, and 3) glucose promotes passage of cells through early G1 by increasing the expression of several key cell cycle regulatory proteins that normally inhibit RB function.

2DG enhances the susceptibility of breast cancer cells to doxorubicin

“…These findings support previous studies, showing 2DG-induced growth inhibition and cytotoxicity in MDA-MB231 cells [32], and FaDu cells [34], accompanied by increases in parameters indicative of oxidative stress and these effects were enhanced with BSO treatment. Furthermore, our results were consistent with a previous study by Singh et al (1999) showing that the growth rate of rapidly dividing DU145 prostate cancer cells depend on high levels of glucose consumption, whereas the growth rate of relatively slow-growing LNCaP cells are much less dependent on glucose [35]. They found a direct correlation between glycolytic capacity and degree of growth inhibition in response to glucose deprivation for these two cell lines.…”

Combined Treatment with 2-Deoxy-D-Glucose and Doxorubicin Enhances the in Vitro Efficiency of Breast Cancer Radiotherapy

“…These findings support previous studies, showing 2DG-induced growth inhibition and cytotoxicity on MDA-MB231 cells (Andringa et al, 2006), and on FaDu cells (Simons et al, 2007). Furthermore, our results were consistent with a previous study by Singh et al (Singh et al, 1999), showing that the growth rate of rapidly dividing DU145 prostate cancer cells depend on high levels of glucose consumption, whereas the growth rate of relatively slow-growing LNCaP cells are much less dependent on glucose (Singh et al, 1999). They found a direct correlation between glycolytic capacity and degree of growth inhibition in response to glucose deprivation for the cell lines.…”

Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer

“…10 In vitro study also suggested that glucose may not be required for androgen-dependent prostate cancer cells because LNCaP cells can grow at control rates even in the presence of only 0.05 g/l glucose. 11 As rapid cell proliferation in malignant tumors is associated with increased energy supply, if glucose consumption is not elevated in prostate cancer, alterative metabolic approach, especially fatty acid oxidation may exist dominantly to provide bioenergy for abnormal cells proliferation and growth.…”