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

Tariq Shah, Ioannis Stasinopoulos, Flonne Wildes, Samata Kakkad, Dmitri Artemov, Zaver M. Bhujwalla

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)746-754
Number of pages9
JournalNMR in biomedicine
Volume25
Issue number5
DOIs
StatePublished - 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

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