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¹ Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY and ² Department of Pathology, University of the Ryukyus Faculty of Medicine, Okinawa, Japan

Requests for Reprints: I. Bernard Weinstein, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, HHSC-1509, 701 West 168th Street, New York, NY 10032. Phone: (212) 305-6921; Fax: (212) 305-6889. E-mail: ibw1{at}columbia.edu

Acyclic retinoid (ACR), a novel synthetic retinoid, has recently been demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and this effect was associated with decreased expression of cell cycle-related molecules. These results, taken together with previous in vitro and clinical studies with ACR, suggest that this agent may be useful in the chemoprevention and therapy of hepatoma and possibly other human malignancies. In the present study, we further examined the molecular effects of ACR on the HepG2 human hepatoma cell line, focusing on the expression of nuclear retinoid receptors and the cell cycle inhibitor protein p21^CIP1. Reverse transcription-PCR assays and Western blot analyses indicated that these cells express retinoic acid receptors (RARs) , ß, and , retinoid X receptors (RXRs) and ß, and peroxisome proliferator-activated receptors (PPAR) mRNA. Treatment with ACR caused a rapid induction within 3 h of RARß mRNA and the related protein, but there was no significant change in the levels of the mRNA or proteins for RARs and , RXRs and ß, and PPAR. There was also a rapid increase in p21^CIP1 mRNA and protein in HepG2 cells treated with ACR, and this induction occurred via a p53-independent mechanism. In transient transfection reporter assays, we cotransfected the retinoic acid response element-chloramphenicol acetyltransferase (CAT) reporter gene into HepG2 cells together with a RARß expression vector. RARß expression markedly stimulated CAT activity (up to about 4-fold) after the addition of ACR. However, CAT activity in the presence of ACR was only about 2-fold higher than that in the absence of ACR, when cells were cotransfected with RARs and or RXR. These findings suggest that the growth inhibitory effects of ACR are mediated at least in part through RARß and that both RARß and p21^CIP1 play critical roles in the molecular mechanisms of growth inhibition induced by ACR.

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Received 7/21/03; revised 12/ 2/03; accepted 12/ 4/03.

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