Sphingosine kinase regulates hepatoma cell differentiation: roles of hepatocyte nuclear factor and retinoid receptor

Biochem Biophys Res Commun. 2001 Aug 31;286(4):673-7. doi: 10.1006/bbrc.2001.5451.

Abstract

In hepatoma Huh-7 cells, inhibition of sphingosine kinase (SphK) activity by N,N-dimethylsphingosine (DMS) resulted in up-regulated production of liver-specific serum proteins including albumin and alpha-fetoprotein (AFP). The changes in these protein levels coincided well with those of two liver-enriched transcription factors, hepatocyte nuclear factor (HNF)-1 and -4, which regulate a number of liver-specific genes at the transcriptional level. Moreover, DMS induced the expression of retinoic acid receptor-alpha and retinoid X receptor-alpha. In DMS-treated cells, 9-cis retinoic acid (RA) further enhanced HNF-4alpha and albumin expression but it inhibited AFP accumulation. These results suggest that activation of SphK disengages cells from their liver-specific phenotype, and that 9-cis RA further induces differentiation of hepatoma cells when SphK activity is inhibited.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alitretinoin
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carcinoma, Hepatocellular
  • Cell Differentiation
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Hepatocyte Nuclear Factor 4
  • Hepatocytes / metabolism*
  • Humans
  • Liver / metabolism
  • Lysophospholipids*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Nuclear Proteins*
  • Phosphoproteins / physiology*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*
  • Receptors, Retinoic Acid / physiology*
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • Serum Albumin / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Transcription Factors / physiology*
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured
  • alpha-Fetoproteins / metabolism

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • HNF1A protein, human
  • HNF1B protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Lysophospholipids
  • MLX protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • Serum Albumin
  • Transcription Factors
  • alpha-Fetoproteins
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • Alitretinoin
  • sphingosine 1-phosphate
  • Tretinoin
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • N,N-dimethylsphingosine
  • Sphingosine