Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2.
Epidemiological investigations suggest that chronic lung inflammation increases lung cancer risk. Pharmacologic and genetic evidence in mouse models indicates that lipid mediators released during pulmonary inflammation enhance lung tumor formation. Cytosolic phospholipase A2 (cPLA2) catalyzes arachidonic acid (AA) release from membrane phospholipids. AA can then lead to the synthesis of several classes of lipid mediators, including prostaglandin (PG) biosynthesis through the cyclooxygenase (COX) pathway. We investigated a role for cPLA2 in mouse lung tumorigenesis by using mice genetically deficient in cPLA2. After multiple urethane injections into cPLA2 null mice and wild-type littermates, the number of lung tumors was determined. cPLA2 null mice developed 43% fewer tumors (from 16 +/- 2 to 9 +/- 2 tumors/mouse; P < 0.05) than wild-type littermates. cPLA2, COX-1, COX-2 and microsomal prostaglandin E2 synthase (mPGES), examined by immunohistochemistry, are present in alveolar and bronchiolar epithelia and in alveolar macrophages in lungs from naive mice and tumor-bearing mice. Tumors express higher levels of each of these four enzymes than control lungs, as determined by immunoblotting. No differences were detected in the contents of COX-1, COX-2 and mPGES between wild-type and cPLA2 null mice. Although the steady-state levels of prostaglandin E2 and prostaglandin I2 in lung tissue extracts prepared from wild-type or cPLA2 (-/-) mice were not significantly different, both prostaglandins markedly increased in tumors from wild-type mice, an increase that was significantly blunted in tumors from cPLA2 (-/-) mice. These results demonstrate a role for cPLA2 in mouse lung tumorigenesis that may be mediated by decreased prostaglandin synthesis.
Meyer
Amy M
AM
Department of Pharmacology, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA.
Dwyer-Nield
Lori D
LD
Hurteau
Gregory J
GJ
Keith
Robert L
RL
O'Leary
Eileen
E
You
Ming
M
Bonventre
Joseph V
JV
Nemenoff
Raphael A
RA
Malkinson
Alvin M
AM
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000483:Alleles; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology*; D015232:Dinoprostone / Q000378:metabolism; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007249:Inflammation; D007527:Isoenzymes / Q000378:metabolism; D050356:Lipid Metabolism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D010741:Phospholipases A / Q000235:genetics*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D016718:Arachidonic Acid; D015121:6-Ketoprostaglandin F1 alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone