Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-A^уMice

Abstract

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferatoractivated receptorγ (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-A y 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-A y 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.

Ay allele promotes azoxymethane‐induced colorectal carcinogenesis by macrophage migration in hyperlipidemic/diabetic KK mice

“…Long‐term treatment with long‐acting insulin on C57BL/KsJ‐ db/db mice, which lack a leptin receptor, revealed that insulin increases colonic epithelial cell proliferation, and formation of ACF . Moreover, the anti‐insulin resistant medicine pioglitazone prevented ACF development in KK‐ A y mice through improvement of serum insulin levels, and increase of p27 and p53 mRNA levels in the colorectal mucosa . Hence, it seems likely that hyperinsulinemia in the KK‐ A y and KK mice enhanced the development of AOM‐induced ACF in the present study.…”

“…(10)(11)(12) Moreover, the anti-insulin resistant medicine pioglitazone prevented ACF development in KK-A y mice through improvement of serum insulin levels, and increase of p27 and p53 mRNA levels in the colorectal mucosa. (13) Hence, it seems likely that hyperinsulinemia in the KK-A y and KK mice enhanced the development of AOM-induced ACF in the present study. In addition, hyperglycemia and hypertriglyceridemia may also contribute to the development of ACF.…”

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target

“…PPAR gamma is also present in other tissues, such as breast [70,71], colon [72][73][74], lung [75,76], ovary [77,78], prostate [79,80] and thyroid [81,82] wherein it mediates several specific functions, such as early development [83], cell proliferation [84], differentiation [85], apoptosis [86], and metabolic homeostasis [87]. Many investigators [88][89][90][91][92][93][94][95][96][97] reported that PPAR gamma was also involved in the control of transcriptional regulation of autophagy.…”

Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

“…There is significant evidence from models of diabetes, arthritis, atherosclerosis, Parkinson’s disease, Alzheimer’s disease and others that administration of PPAR natural ligands and synthetic agonists has anti-inflammatory effects. Specific reductions in proinflammatory chemokines and cytokines has been observed in numerous cells types: renal cells (Wang et al, 2011; Lu et al, 2013), vascular smooth muscle cells (Marchesi et al, 2013), adipocytes (Guri et al, 2008; Ueno et al, 2012), mesothelial cells (Sauter et al, 2012), epithelial cells (Neri et al, 2011), splenocytes (Bassaganya-Riera et al, 2011), monocytes/macrophages (Han et al, 2005; Tanaka et al, 2005; Hounoki et al, 2008; Liu et al, 2012), astrocytes (Lee et al, 2008, 2012), and microglia (Kim et al, 2012). …”