Inhibition of 20 S and 26 S proteasome activity by lithium chloride: impact on the differentiation of leukemia cells by all-trans retinoic acid

J Biol Chem. 2001 Nov 16;276(46):42722-7. doi: 10.1074/jbc.M106583200. Epub 2001 Sep 12.

Abstract

Lithium affects several enzymatic activities, however, the molecular mechanisms of lithium actions are not fully understood. We previously showed that LiCl interacts synergistically with all-trans-retinoic acid to promote terminal differentiation of WEHI-3B D(+) cells, a phenomenon accompanied by the recovery of the retinoid-induced loss of retinoic acid receptor alpha protein pools. Here, we demonstrate the effects of LiCl on proteasome-dependent degradation of retinoic acid receptor alpha proteins. LiCl alone, or in combination with all-trans-retinoic acid, increased cellular levels of ubiquitinated retinoic acid receptor alpha and markedly reduced chymotryptic-like activity of WEHI-3B D(+) 20 S and 26 S proteasome enzymes. Neither KCl nor all-trans-retinoic acid affected enzyme activity, whereas NaCl produced a modest reduction at relatively high concentrations. In addition, LiCl inhibited 20 S proteasome chymotryptic-like activity from rabbits but had no effect on tryptic-like activity of the 26 S proteasome. This effect has significant consequences in stabilizing the retinoic acid receptor alpha protein levels that are necessary to promote continued differentiation of leukemia cells in response to all-trans-retinoic acid. In support of this concept, combination of proteasome inhibitors beta-clastolactacystin or benzyloxycarbonyl-Leu-Leu-Phe with all-trans-retinoic acid increased differentiation of WEHI-3B D(+) cells in a manner that was analogous to the combination of LiCl and all-trans-retinoic acid.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Blotting, Western
  • Cell Differentiation
  • Cell Line
  • Chymotrypsin / pharmacology
  • Cysteine Endopeptidases
  • Humans
  • Kinetics
  • Lactones / pharmacology
  • Leukemia / metabolism
  • Lithium Chloride / pharmacology*
  • Multienzyme Complexes / antagonists & inhibitors*
  • Oligopeptides / pharmacology
  • Peptide Hydrolases / metabolism*
  • Precipitin Tests
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Biosynthesis
  • Rabbits
  • Receptors, Retinoic Acid / chemistry
  • Retinoic Acid Receptor alpha
  • Time Factors
  • Tretinoin / pharmacology*
  • Trypsin / pharmacology
  • Tumor Cells, Cultured
  • Ubiquitin / metabolism

Substances

  • Adjuvants, Immunologic
  • Lactones
  • Multienzyme Complexes
  • Oligopeptides
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Ubiquitin
  • benzyloxycarbonyl-leucyl-leucyl-phenylalanine
  • clasto-lactacystin beta-lactone
  • Tretinoin
  • Peptide Hydrolases
  • Chymotrypsin
  • Trypsin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Lithium Chloride