Journal Article

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

Rie Matsushima-Nishiwaki, Masataka Okuno, Yukihiko Takano, Soichi Kojima, Scott L. Friedman and Hisataka Moriwaki

in Carcinogenesis

Volume 24, issue 8, pages 1353-1359
Published in print August 2003 | ISSN: 0143-3334
Published online August 2003 | e-ISSN: 1460-2180 | DOI:
Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid

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We have reported previously that acyclic retinoid, a synthetic retinoid X receptor α (RXRα)-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 RXRα-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRα. Here, we show that acyclic retinoid restores the function of RXRα in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRα. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRα 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.

Keywords: 4HPR, 4-hydroxyphenyl retinamide; 9cRA, 9-cis RA, retinoic acid; atRA, all-transRA; CRBP, cellular retinol-binding protein; EGF, epidermal growth factor; Erk, extracellular signal-regulated kinase; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCC, hepatocellular carcinoma; MAP kinase, mitogen-activated protein kinase; MKP-1, MAP kinase phosphatase-1; RAR, retinoic acid receptor; RXR, retinoid X receptor; RXRE, RXR-response element; TGF-α, transforming growth factor-α; VDR, vitamin D receptor

Journal Article.  5383 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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