Inhibition of 20 S and 26 S proteasome activity by lithium chloride: impact on the differentiation of leukemia cells by all-trans retinoic acid.
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.
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Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Sartorelli
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D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D002918:Chymotrypsin / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D007938:Leukemia / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D014176:Protein Biosynthesis; D011817:Rabbits; D018168:Receptors, Retinoic Acid / Q000737:chemistry; D000072482:Retinoic Acid Receptor alpha; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D014357:Trypsin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007783:Lactones; D009097:Multienzyme Complexes; D009842:Oligopeptides; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D025801:Ubiquitin; C442222:benzyloxycarbonyl-leucyl-leucyl-phenylalanine; C098869:clasto-lactacystin beta-lactone; D014212:Tretinoin; D010447:Peptide Hydrolases; D002918:Chymotrypsin; D014357:Trypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D018021:Lithium Chloride