Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand

Cancer Letters
Tomohiko OhnoHisataka Moriwaki

Abstract

Abnormalities in the expression and function of retinoid X receptor (RXR), a master regulator of the nuclear receptor superfamily, are associated with the development of hepatocellular carcinoma (HCC). Dysfunction of farnesoid X receptor (FXR), one of the nuclear receptors that forms a heterodimer with RXR, also plays a role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), a synthetic retinoid targeting RXRα, plus GW4064, a ligand for FXR, on the growth of human HCC cells. We found that ACR and GW4064 preferentially inhibited the growth of HLE, HLF, and Huh7 human HCC cells in comparison with Hc normal hepatocytes. The combination of 1μM ACR plus 1μM GW4064 synergistically inhibited the growth of HLE cells by inducing apoptosis. The combined treatment with these agents acted cooperatively to induce cell cycle arrest in the G(0)/G(1) phase and inhibit the phosphorylation of RXRα, which is regarded as a critical factor for liver carcinogenesis, through inhibition of ERK and Stat3 phosphorylation. This combination also increased the expression levels of p21(CIP1) and SHP mRNA, while decreasing the levels of c-myc and cyclin D1 mRNA in HLE cells. In addition, a reporter assay indicat...Continue Reading

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Citations

Aug 7, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jian-Hua Duan, Long Fang
Dec 17, 2014·Cellular and Molecular Life Sciences : CMLS·Claire MazuyPhilippe Lefebvre
Jun 24, 2018·The Journal of Biological Chemistry·Weili ZhengYong Li
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Jun 24, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Chiara DegirolamoAntonio Moschetta
Sep 5, 2014·Experimental and Therapeutic Medicine·Jun LiuLian-Xi Qu
Jan 14, 2021·Scientific Reports·Tsuneyuki MiyazakiMasahito Shimizu
Apr 28, 2020·European Journal of Medicinal Chemistry·Yu YangLiang Ouyang
Feb 26, 2021·Biochemical and Biophysical Research Communications·Jing GuoJunhui Yu

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