Abstract
Mutations in the p53 gene are the most frequently observed genetic lesions in human cancers. Human cancers that contain a p53 mutation are more aggressive, more apt to metastasize, and more often fatal. p53 controls numerous downstream targets that can influence various outcomes such as apoptosis, growth arrest, and DNA repair. Based on previous observations using (1)H magnetic resonance spectroscopy (MRS), we have identified choline phospholipid metabolite intensities typical of increased malignancy. Here we have used (1)H MRS to characterize the choline phospholipid metabolite levels of p53(+/ +) and p53(-/-) cells, and demonstrated that loss of p53 function results in increased phosphocholine and total choline. These data suggest that the increased malignancy of cancer cells resulting from loss of p53 may be mediated, in part, through the choline phospholipid pathway.
Highlights
The tumor suppressor p53 controls numerous downstream targets that can impact upon apoptosis, transient growth arrest, and sustained growth arrest or senescence [1]
Proton spectra of HCT116 p53 À/À and p53+/+ colon cancer cells were typical of malignant cells, exhibiting high PC and low GPC (Figure 1)
Colon cancer cells exhibited an increase of PC and total CHO compared with wt p53+/+ cells
Summary
The tumor suppressor p53 controls numerous downstream targets that can impact upon apoptosis, transient growth arrest, and sustained growth arrest or senescence [1]. We have previously shown that in human mammary epithelial cells (HMECs), both total choline (CHO) and phosphocholine (PC) levels increased significantly with progression to the malignant phenotype [3]. Another study using normal and malignant human prostatic cells showed that tumor cells exhibited significantly higher PC as well as glycerophosphocholine (GPC) levels compared to normal cells [4]. We demonstrated that a metastasis suppressor gene (nm-23) transfected breast cancer cells, and transgene tumors derived from these cells, showed significantly lower ratios of PC to GPC [6]. Treatment of HMECs with the nonsteroidal anti-inflammatory drug, indomethacin, mimicked the effects of nm-23 transfection, and altered the choline phospholipid metabolite intensities to those more representative of a less malignant phenotype, with lower PC/GPC [7]
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