Abstract
We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-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 RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha 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.
Highlights
Retinoids are prime candidates for cancer chemoprevention, as they have profound effects on cell growth, apoptosis and differentiation [1]
Because malfunction of retinoid X receptor a (RXRa) is due to phosphorylation at a serine residue [9], we first examined if acyclic retinoid might dephosphorylate a phosphoserine of RXRa
These results suggest that HuH7 cells are refractory to 9-cis RA (9cRA), but sensitive to acyclic retinoid, in regulating the activation of extracellular signal-regulated kinase (Erk) 1/2 and subsequent RXRa phosphorylation
Summary
Retinoids are prime candidates for cancer chemoprevention, as they have profound effects on cell growth, apoptosis and differentiation [1]. We documented previously a local depletion of retinoid in human HCC tissues due to its rapid conversion to an Abbreviations: 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-a, transforming growth factor-a; VDR, vitamin D receptor. Acetylation of histones leads to nucleosomal repulsion and chromatin decondensation, which is thought to be indispensable for the transcriptional activation by retinoid receptor
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