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Carcinogenesis Advance Access published online on May 22, 2003
Carcinogenesis, doi:10.1093/carcin/bgg090
© 2003 by Oxford University Press
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© 2003 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid

Rie Matsushima-Nishiwaki 1, Masataka Okuno 1*, Yukihiko Takano 1, Soichi Kojima 2, Scott L. Friedman 3, Hisataka Moriwaki 1

1 First Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan
2 Molecular Cellular Pathology Research Unit, RIKEN, Wako, Japan
3 Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY

* Corresponding author. E-mail: mokuno{at}cc.gifu-u.ac.jp.

Received 21 August 2002 ; revised 8 April 2003 ; accepted 9 April 2003

Abstract

We have previously reported that acyclic retinoid, a synthetic retinoid X receptor {alpha} (RXR{alpha})-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXR{alpha}-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXR{alpha}. Here, we show that acyclic retinoid restores the function of RXR{alpha} in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXR{alpha}. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXR{alpha} phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously downregulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.


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