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Modeling Colitis-Associated Cancer with Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS)
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Modeling Colitis-Associated Cancer with Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS)

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Azoxymethane protects intestinal stem cells and reduces crypt epithelial mitosis through a COX-1-dependent mechanism

Terrence E Riehl1, Robert J George, Mark A Sturmoski

  • 1Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

American Journal of Physiology. Gastrointestinal and Liver Physiology
|October 14, 2006
PubMed

Insights

Azoxymethane (AOM) DNA damage triggers a prosurvival response in intestinal stem cells, mediated by cyclooxygenase-1 (COX-1). This suggests COX-1 is crucial for early colon cancer development and a potential therapeutic target.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Cancer Research

Background:

  • Azoxymethane (AOM) is a carcinogen that induces DNA damage, leading to intestinal and colonic tumors in rodents.
  • AOM treatment elicits a prosurvival response in intestinal stem cells within hours.
  • Cyclooxygenase (COX) enzymes are implicated in inflammation and cancer development.

Purpose of the Study:

  • To investigate the role of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in the early prosurvival response of intestinal stem cells to Azoxymethane (AOM).
  • To determine the involvement of COX-1-derived prostaglandin E2 (PGE2) in mediating AOM-induced effects on intestinal stem cell survival, apoptosis, and mitosis.

Main Methods:

  • Utilized wild-type (WT), COX-1 knockout (COX-1(-/-)), and COX-2 knockout (COX-2(-/-)) mice.
  • Administered AOM (10 mg/kg) and evaluated intestinal crypt stem cell survival using colony formation assays.
  • Assessed COX-1 mRNA and protein expression, PGE2 synthesis, intestinal apoptosis, and crypt mitotic figures via immunohistochemistry and other methods.

Main Results:

  • AOM treatment significantly increased intestinal crypt stem cell survival in WT mice.
  • Stem cell survival increased in COX-2(-/-) mice but not in COX-1(-/-) mice, indicating a critical role for COX-1.
  • COX-1 expression and PGE2 synthesis were upregulated post-AOM, with COX-1 localized to crypt epithelial cells. AOM-induced reduction in mitosis was reversed in COX-1(-/-) mice, while apoptosis levels remained similar.

Conclusions:

  • Cyclooxygenase-1 (COX-1)-derived prostaglandin E2 (PGE2) plays a significant role in the early phase of intestinal tumorigenesis following DNA damage induced by Azoxymethane (AOM).
  • COX-1 mediates the prosurvival response and affects mitotic activity in intestinal stem cells after AOM exposure.
  • COX-1 represents a potential therapeutic target for colon cancer in models involving DNA damage.

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