Influence of myeloperoxidase on colon tumor occurrence in inflamed versus non-inflamed colons of Apc(Min/+) mice.
Control of colorectal cancer needs to be tailored to its etiology. Tumor promotion mechanisms in colitis-associated colon cancer differ somewhat from the mechanisms involved in hereditary and sporadic colorectal cancer. Unlike sporadic or inherited tumors, some experimental models show that colitis-associated colon tumors do not require cyclooxygenase (COX) expression for progression, and non-steroidal anti-inflammatory drugs (NSAIDs) which prevent sporadic or inherited colon cancer do not prevent colitis-associated colon cancer. We report that myeloperoxidase (MPO), an ancestor of the COX isoenzymes, is a determinant of colitis-associated colon tumors in Apc(Min/+) mice. During experimentally induced colitis, inhibition of MPO by resorcinol dampened colon tumor development. Conversely, in the bowels of Apc(Min/+) mice without colitis, resorcinol administration or 'knockout' of MPO gene coincided with a slight, but discernible increase in colon tumor incidence. Acrolein, a by-product of MPO catalysis, formed a covalent adduct with the phosphatase tensin homolog (PTEN) tumor suppressor and enhanced the activity of the Akt kinase proto-oncogene in vitro and in vivo. Thus, MPO may be an important determinant of diet and inflammation on colon cancer risk via its effect on endogenous exposure to oxidants and acrolein. We propose a hypothetical model to explain an apparent dichotomy between colon tumor occurrence and MPO inhibition in inflamed versus non-inflamed colons.
School of Medicine, University of Jordan, Amman 11942, Jordan. Electronic address: mazin@fulbrightmail.org.
Mazin
M
Al-Salihi
Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
Ethan
E
Reichert
Kansas City University of Medicine & Biosciences, Department of Pharmacology, 1750 Independence Avenue, Kansas City, MO 64106, USA. Electronic address: ffitzpatrick@kcumb.edu.
F A
FA
Fitzpatrick
D000171:Acrolein / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D007249:Inflammation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009195:Peroxidase / Q000172:deficiency / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D012967:Sodium Dodecyl Sulfate
D034741:RNA, Small Interfering; D012118:Resorcinols; D012967:Sodium Dodecyl Sulfate; D000171:Acrolein; D009195:Peroxidase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C031389:resorcinol
Colitis; Colon cancer; Inflammation; Myeloperoxidase