15-Deoxy-delta(12,14)-prostaglandin J(2) down-regulates CXCR4 on carcinoma cells through PPARgamma- and

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Cynthia Lee Richard1, Erica Lauren Lowthers, Jonathan Blay

  • 1Department of Pharmacology, Faculty of Medicine, Sir Charles Tupper Building, Dalhousie University, Halifax, Nova Scotia, Canada.

Experimental Cell Research
|August 21, 2007
PubMed

Insights

Prostaglandins like 15dPGJ(2) in colorectal tumors can decrease CXCR4 expression on cancer cells. This occurs via nuclear receptor PPARgamma and NFkappaB pathways, potentially impacting tumor expansion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The chemokine receptor CXCR4 is crucial for colorectal cancer (CRC) metastasis.
  • Eicosanoids within the tumor microenvironment may regulate CXCR4 expression on CRC cells.

Purpose of the Study:

  • To investigate how eicosanoids in the CRC tumor microenvironment regulate CXCR4 expression on cancer cells.
  • To elucidate the molecular mechanisms, including PPARgamma and NFkappaB pathways, involved in this regulation.

Main Methods:

  • Treatment of human colorectal carcinoma cells with various prostaglandins (PGE(2), PGA(2), PGD(2), PGJ(2), 15dPGJ(2)).
  • Assessment of CXCR4 receptor expression and mRNA levels.
  • Utilized PPARgamma agonists (rosiglitazone) and antagonists (GW9662, T0070907).
  • Investigated the role of NFkappaB using cyclopentenone prostaglandins and immunolocalization studies.

Main Results:

  • Prostaglandins PGD(2), PGJ(2), and 15dPGJ(2) significantly down-regulated CXCR4 expression and mRNA.
  • 15dPGJ(2) mediated CXCR4 down-regulation through both PPARgamma and NFkappaB pathways.
  • The cyclopentenone structure of prostaglandins was important for NFkappaB inhibition.
  • 15dPGJ(2) interfered with NFkappaB p50 nuclear localization.

Conclusions:

  • 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ(2)) down-regulates CXCR4 on colorectal cancer cells.
  • This down-regulation involves activation of the nuclear receptor PPARgamma and inhibition of NFkappaB.
  • 15dPGJ(2) in the tumor microenvironment may influence colorectal cancer progression by modulating CXCR4.

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