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Carcinogenesis Advance Access originally published online on May 22, 2003
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Carcinogenesis, Vol. 24, No. 8, 1353-1359, August 2003
© 2003 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Rie Matsushima-Nishiwaki1, Masataka Okuno1,4, Yukihiko Takano1, Soichi Kojima2, Scott L. Friedman3 and Hisataka Moriwaki1

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, USA

4 To whom correspondence should be addressed Email: mokuno{at}cc.gifu-u.ac.jp

We have reported previously 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 down-regulated 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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