title: Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethane-induced colon aberrant crypt foci in KK-Ay mice.
abstract: Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator- activated receptor γ(PPARγ) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ay obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.
authors.affiliation: Division of Cancer Prevention Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Ueno
authors.forename: Naoya
authors.initials: N
authors.lastname: Teraoka
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakano
authors.forename: Mami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Gen
authors.initials: G
authors.lastname: Fujii
authors.forename: Masami
authors.initials: M
authors.lastname: Komiya
authors.forename: Akinori
authors.initials: A
authors.lastname: Yanaka
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mutoh
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000188:drug therapy*; D054392:Adipokines / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000209:etiology; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D054392:Adipokines; D015415:Biomarkers; D002273:Carcinogens; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D008055:Lipids; D047495:PPAR gamma; D045162:Thiazolidinediones; D001397:Azoxymethane; D000077205:Pioglitazone