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.
Highlights
Colorectal cancer is one of the common cancers in developed countries including Japan
We investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Agouti yellow gene (Ay) obesity and diabetes model mice, and tried to clarify mechanisms by which the peroxisome proliferatoractivated receptorγ (PPARγ) ligand inhibits ACF development
Pioglitazone treatment decreased the number of AOM-induced ACF in obese KK-Ay mice
Summary
Colorectal cancer is one of the common cancers in developed countries including Japan. Many epidemiological studies have suggested colorectal cancer correlates with obesity, a high-fat diet and hyperlipidemia, especially, hypertriglyceridemia and high levels of low-density lipoprotein cholesterol (Le Marchand et al, 1997; Bruce et al, 2000). Among adipocytokines, increased levels of leptin, plasminogen activator inhibitor-1 (PAI-1), and decreased levels of adiponectin are demonstrated to play an important role in colorectal carcinogenesis (van Kruijsdijk et al, 2009). Serum pro-inflammatory adipocytokines such as interleukin-6 (IL-6), leptin and Pai-1 in KK-Ay mice were elevated and adiponectin was decreased compared to those in lean C57BL/6J mice. Serum leptin levels were the highest in KKAy mice. Those features of KK-Ay mice could explain their high susceptibility to AOM-induced colorectal carcinogenesis, and suggests they could be useful to evaluate chemopreventive agents against obesityassociated colorectal cancer
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