Abstract
The expression of cyclooxygenase-2 (COX-2) is observed in approximately 40% of breast cancers. A major product of the COX-2-catalyzed reaction, prostaglandin E 2, is an inflammatory mediator that participates in several biological processes, and influences invasion, vascularization and metastasis. Using noninvasive MRI and MRS, we determined the effect of COX-2 downregulation on the metabolism and invasion of intact poorly differentiated MDA-MB-231 human breast cancer cells stably expressing COX-2 short hairpin RNA. Dynamic tracking of invasion, extracellular matrix degradation and metabolism was performed with an MRI- and MRS-compatible cell perfusion assay under controlled conditions of pH, temperature and oxygenation over the course of 48h. COX-2-silenced cells exhibited a significant decrease in invasion relative to parental cells that was consistent with the reduced expression of invasion-associated matrix metalloproteinase genes and an increased level of the tissue inhibitor of metalloproteinase-1. We identified, for the first time, a role for COX-2 in mediating changes in choline phospholipid metabolism, and established that choline kinase expression is partly dependent on COX-2 function. COX-2 silencing resulted in a significant decrease in phosphocholine and total choline that was detected by MRS. In addition, a significant increase in lipids, as well as lipid droplet formation, was observed. COX-2 silencing transformed parental cell metabolite patterns to those characteristic of less aggressive cancer cells. These new functional roles of COX-2 may identify new biomarkers and new targets for use in combination with COX-2 targeting to prevent invasion and metastasis.
Original language | English (US) |
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Pages (from-to) | 746-754 |
Number of pages | 9 |
Journal | NMR in biomedicine |
Volume | 25 |
Issue number | 5 |
DOIs | |
State | Published - May 2012 |
Keywords
- Breast cancer
- COX-2
- Choline kinase
- Invasion
- Lipid droplets
- MRS
ASJC Scopus subject areas
- Molecular Medicine
- Radiology Nuclear Medicine and imaging
- Spectroscopy