Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice

Abstract

Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) a due to phosphorylation by Ras/ MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRa, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J-þLepr db /þLepr db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared with basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK (extracellular signalregulated kinase) and RXRa proteins in the livers of experimental mice. It also increased the expression of RARb and p21 CIP1 mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRa function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin decreased by ACR treatment, whereas the quantitative insulin sensitivity check index (QUICKI) values increased, indicating improved insulin sensitivity. The serum levels of TNF-a and the expression levels of TNF-a, IL-6, and IL-1b mRNA in the livers of DENtreated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. ACR may be, therefore, useful in the chemoprevention of obesity-related HCC.

Obesity and cancer—mechanisms underlying tumour progression and recurrence

“…53 Treatment with these agents decreased levels of Stat3 protein, which is a downstream mediator of IL-6 signalling. Total serum levels of both IL-6 and TNF were decreased in the acyclic-retinoid-treated mice, suggesting that these compounds prevent HCC tumourigenesis in HFD-fed mice through inhibition of the IL-6–Stat3 axis.…”

Retinoids and rexinoids in cancer prevention: from laboratory to clinic

“…Acyclic retinoids were found to be effective specifically for the prevention of hepatocellular carcinomas [127]. Long-term administration of acyclic retinoids significantly inhibited hepatic adenomas through inhibition of Ras and phosphorylation of ERK, and increased expression of RARβ and p21 [128]. The synthetic rexinoid analog, 9- cis UAB30 has been tested as a breast cancer prevention agent.…”

Hepatic metabolism of retinoids and disease associations

“…Many studies investigating the mechanisms of ACR in the chemoprevention of HCC have shown that the efficacy of ACR is mediated through suppression of Ras/MAP kinase signal transduction and reducing phosphorylated RXRα, which is resistant to proteasomal degradation and accumulates in the nucleus. This later effect interferes with normal RXRα functions and promots tumor growth [135, 140–143]. Other research, involving cell lines and animals, has demonstrated that ACR may suppress HCC by activating RARβ and inducing p21 expression [143–146].…”

“…This later effect interferes with normal RXRα functions and promots tumor growth [135, 140–143]. Other research, involving cell lines and animals, has demonstrated that ACR may suppress HCC by activating RARβ and inducing p21 expression [143–146]. This suppresses transforming growth factor α (TGFα) expression [147, 148] and modulates fibroblast growth factor signaling [149].…”