Noninvasive imaging identifies new roles for cyclooxygenase‐2 in choline and lipid metabolism of human breast cancer cells

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 48 h. 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.