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Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy
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Deletion of cytosolic phospholipase A(2) suppresses Apc(Min)-induced tumorigenesis

K H Hong1, J C Bonventre, E O'Leary

  • 1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 29, 2001
PubMed

Insights

Deleting cytosolic phospholipase A2 (cPLA2) significantly reduces intestinal tumors in mice by limiting arachidonic acid (AA) supply for cyclooxygenase-2 (COX-2). This suggests prostaglandin (PG) synthesis inhibition is key to NSAID cancer therapy.

Area of Science:

  • Gastroenterology
  • Oncology
  • Molecular Biology

Background:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) show potential for colon cancer therapy, but their mechanism of action is debated.
  • NSAIDs inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin (PG) synthesis, a proposed anti-tumor mechanism.
  • Conflicting studies on phospholipase A2 (PLA2) mutations suggest PG-independent roles or highlight precursor availability, like arachidonic acid (AA).

Purpose of the Study:

  • To investigate the role of arachidonic acid (AA) in intestinal tumorigenesis.
  • To clarify the specific contribution of cytosolic phospholipase A2 (cPLA2) in providing AA for cyclooxygenase-2 (COX-2).
  • To determine if AA reduction, via cPLA2 inhibition, impacts tumor development.

Main Methods:

  • Utilized Apc(Min/+) mice, a model for intestinal polyposis.
  • Generated and analyzed mice with targeted deletions of the group IV cytosolic phospholipase A2 (cPLA2) locus (Pla2g4).
  • Compared tumor numbers in Apc(Min/+), cPLA2(-/-) mice versus Apc(Min/+), cPLA2(+/-) and Apc(Min/+), cPLA2(+/+) littermates.

Main Results:

  • Apc(Min/+), cPLA2(-/-) mice exhibited an 83% reduction in intestinal tumor number compared to controls.
  • This reduction mirrors the phenotype observed in COX-2 knockout mice.
  • The findings indicate cPLA2 is a primary source of AA for intestinal COX-2.

Conclusions:

  • Deletion of cPLA2 significantly suppresses intestinal tumorigenesis.
  • The protective effect is attributed to reduced AA availability for COX-2, leading to decreased PG synthesis.
  • This supports the hypothesis that PG synthesis inhibition is a critical mechanism for NSAID-mediated cancer prevention.

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