title: Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand.
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 indicated that the FXRE promoter activity was significantly increased by treatment with ACR plus GW4064. Our results suggest that ACR and GW4064 cooperatively inhibit RXRα phosphorylation, modulate the expression of FXR-regulated genes, thus resulting in the induction of apoptosis and the inhibition of growth in HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kochi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D012176:Retinoids / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D012176:Retinoids; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064