TY - JOUR
T1 - Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells
AU - Glunde, Kristine
AU - Jie, Chunfa
AU - Bhujwalla, Zaver M.
N1 - Funding Information:
Abbreviations: Cho, free choline; COX, cyclooxygenase; GPC, glycerophosphocholine; HMEC, human mammary epithelial cell; NSAID, nonsteroidal anti-inflammatory drug; MR, magnetic resonance; MRS, magnetic resonance spectroscopy; PC, phosphocholine; PE, phosphoethanolamine; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PtdCho, phosphatidylcholine; tCho, total choline-containing compounds Address all correspondence to: Zaver M. Bhujwalla, PhD, Department of Radiology, Johns Hopkins University School of Medicine, 208C Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: zaver@mri.jhu.edu 1This work was supported by the National Institutes of Health (R01 CA82337). Received 24 February 2006; Revised 16 June 2006; Accepted 19 June 2006.
PY - 2006
Y1 - 2006
N2 - Human mammary epithelial cells (HMECs) exhibit an increase in phosphocholine (PC) and total choline-containing compounds, as well as a switch from high glycerophosphocholine (GPC)/low PC to low GPC/high PC, with progression to malignant phenotype. The treatment of human breast cancer cells with a nonsteroidal anti-inflammatory agent, indomethacin, reverted the high PC/low GPC pattern to a low PC/high GPC pattern indicative of a less malignant phenotype, supported by decreased invasion. Here, we have characterized mechanisms underlying indomethacin-induced alterations in choline membrane metabolism in malignant breast cancer cells and nonmalignant HMECs labeled with [1,2-13C]choline using 1H and 13C magnetic resonance spectroscopy. Microarray gene expression analysis was performed to understand the molecular mechanisms underlying these changes. In breast cancer cells, indomethacin treatment activated phospholipases that, combined with an increased choline phospholipid biosynthesis, led to increased GPC and decreased PC levels. However, in nonmalignant HMECs, activation of the anabolic pathway alone was detected following indomethacin treatment. Following indomethacin treatment in breast cancer cells, several candidate genes, such as interleukin 8, NGFB, CSF2, RHOB, EDN1, and JUNB, were differentially expressed, which may have contributed to changes in choline metabolism through secondary effects or signaling cascades leading to changes in enzyme activity.
AB - Human mammary epithelial cells (HMECs) exhibit an increase in phosphocholine (PC) and total choline-containing compounds, as well as a switch from high glycerophosphocholine (GPC)/low PC to low GPC/high PC, with progression to malignant phenotype. The treatment of human breast cancer cells with a nonsteroidal anti-inflammatory agent, indomethacin, reverted the high PC/low GPC pattern to a low PC/high GPC pattern indicative of a less malignant phenotype, supported by decreased invasion. Here, we have characterized mechanisms underlying indomethacin-induced alterations in choline membrane metabolism in malignant breast cancer cells and nonmalignant HMECs labeled with [1,2-13C]choline using 1H and 13C magnetic resonance spectroscopy. Microarray gene expression analysis was performed to understand the molecular mechanisms underlying these changes. In breast cancer cells, indomethacin treatment activated phospholipases that, combined with an increased choline phospholipid biosynthesis, led to increased GPC and decreased PC levels. However, in nonmalignant HMECs, activation of the anabolic pathway alone was detected following indomethacin treatment. Following indomethacin treatment in breast cancer cells, several candidate genes, such as interleukin 8, NGFB, CSF2, RHOB, EDN1, and JUNB, were differentially expressed, which may have contributed to changes in choline metabolism through secondary effects or signaling cascades leading to changes in enzyme activity.
KW - Anti-inflammatory agent
KW - Breast cancer
KW - Choline compounds
KW - Magnetic resonance spectroscopy
KW - Phospholipids
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U2 - 10.1593/neo.06187
DO - 10.1593/neo.06187
M3 - Article
C2 - 16984733
AN - SCOPUS:33749043078
SN - 1522-8002
VL - 8
SP - 758
EP - 771
JO - Neoplasia
JF - Neoplasia
IS - 9
ER -