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. 2011 Mar;24(1):25-36.
doi: 10.1293/tox.24.25. Epub 2011 Mar 31.

Enhanced Urinary Bladder, Liver and Colon Carcinogenesis in Zucker Diabetic Fatty Rats in a Multiorgan Carcinogenesis Bioassay: Evidence for Mechanisms Involving Activation of PI3K Signaling and Impairment of p53 on Urinary Bladder Carcinogenesis

Naomi Ishii, Min Wei, Anna Kakehashi, Kenichiro Doi, Shotaro Yamano, Masaaki Inaba, Hideki Wanibuchi

Enhanced Urinary Bladder, Liver and Colon Carcinogenesis in Zucker Diabetic Fatty Rats in a Multiorgan Carcinogenesis Bioassay: Evidence for Mechanisms Involving Activation of PI3K Signaling and Impairment of p53 on Urinary Bladder Carcinogenesis

Naomi Ishii et al. J Toxicol Pathol. 2011 Mar.

Abstract

In the present study, modifying effects of diabetes on carcinogenesis induced in type 2 diabetes mellitus model Zucker diabetic fatty (ZDF) rats were investigated using a multiorgan carcinogenesis bioassay. Our re sults demonstrated enhancement of urinary bladder, colon and liver carcinogenesis in ZDF rats treated with five types of carcinogens (DMBDD). Elevated insulin and leptin and decreased adiponectin levels in the serum may be responsible for the high susceptibility of type 2 diabetes mellitus model rats to carcinogenesis in these organs. Possible mechanisms of increased susceptibility of diabetic rats to bladder carcinogenesis could be activation of the PI3K pathway and suppression of p53 in the urothelium in consequence of the above serum protein alterations.

Keywords: PI3K; bladder carcinogenesis; p53; type 2 diabetes mellitus.

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Figures

Fig. 1.
Fig. 1.
Experimental protocol of experiment 1 (DMBDD model).
Fig. 2.
Fig. 2.
Time course of body weight and blood glucose level in experiment 1 (A, B) and experiment 2 (C, D). a P<0.05 vs. control rats of the same genotype.
Fig. 3.
Fig. 3.
Macroscopic view of the urinary bladder in experiment 1. A: DMBDD-treated ZDF rats. B: DMBDD-treated Lean rats.
Fig. 4.
Fig. 4.
Serum levels of insulin, leptin, adiponectin and IGF-1 in ZDF and Lean rats. Data from experiment 1 (A, C, E and G) and experiment 2 (B, D, F and H). Serum concentrations of insulin (A and B), leptin (C and D), adiponectin (E and F) and IGF-1 (G and H) were measured by ELISA. *, ** and ***: P<0.05, P<0.001 and P<0.0001, respectively, vs. Lean rats receiving the same treatment.
Fig. 5.
Fig. 5.
IGF-1 mRNA expression in the liver. * and **: P<0.05 and P<0.001, respectively, vs. Lean rats receiving the same treatment.
Fig. 6.
Fig. 6.
PI3K, p53 and PCNA mRNA expression in the bladder epithelium of BBN-treated rats (experiment 2). *, ** and ***: P<0.05, P<0.001 and P<0.0001, respectively, vs. Lean rats receiving the same treatment. a and aa: P<0.05 and P<0.001, respectively, vs. control rats of the same genotype.
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