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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Antineoplastic Agents / pharmacology*
-
Blotting, Western
-
Carcinoma, Hepatocellular / metabolism
-
Carcinoma, Hepatocellular / pathology*
-
Cell Cycle Proteins*
-
Cell Division / drug effects
-
Dual Specificity Phosphatase 1
-
Humans
-
Immediate-Early Proteins / metabolism
-
Liver Neoplasms / metabolism
-
Liver Neoplasms / pathology*
-
Luciferases / metabolism
-
MAP Kinase Signaling System
-
Mitogen-Activated Protein Kinases / metabolism
-
Mutagenesis, Site-Directed
-
Phosphoprotein Phosphatases*
-
Phosphorylation
-
Phosphoserine / metabolism
-
Protein Phosphatase 1
-
Protein Tyrosine Phosphatases / metabolism
-
Receptors, Retinoic Acid / antagonists & inhibitors
-
Receptors, Retinoic Acid / genetics
-
Receptors, Retinoic Acid / metabolism
-
Response Elements
-
Retinoid X Receptors
-
Transcription Factors / antagonists & inhibitors
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transcription, Genetic
-
Transcriptional Activation / physiology
-
Transfection
-
Tretinoin / analogs & derivatives*
-
Tretinoin / pharmacology*
-
Tumor Cells, Cultured
-
ras Proteins / metabolism
Substances
-
Antineoplastic Agents
-
Cell Cycle Proteins
-
Immediate-Early Proteins
-
Receptors, Retinoic Acid
-
Retinoid X Receptors
-
Transcription Factors
-
Phosphoserine
-
Tretinoin
-
3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid
-
Luciferases
-
Mitogen-Activated Protein Kinases
-
Phosphoprotein Phosphatases
-
Protein Phosphatase 1
-
DUSP1 protein, human
-
Dual Specificity Phosphatase 1
-
Protein Tyrosine Phosphatases
-
ras Proteins