Maintenance of retinoic acid receptor alpha pools by granulocyte colony-stimulating factor and lithium chloride in all-trans retinoic acid-treated WEHI-3B leukemia cells: relevance to the synergistic induction of terminal differentiation.
Previous studies have demonstrated that combinations of all-trans retinoic acid (ATRA) with either granulocyte-colony stimulating factor (G-CSF) or lithium chloride (LiCl) produced synergistic terminal differentiation of WEHI-3B myelomonocytic leukemia (D(+)) cells. It was found that steady-state retinoic acid receptor alpha (RARalpha) protein levels were markedly reduced in these cells after exposure to ATRA. Because the presence of receptors for a hormone ligand is required for its action, differentiation therapy with ATRA may be self-limiting. The combination of G-CSF with ATRA significantly attenuated the loss of RARalpha protein, and synergistic terminal differentiation occurred. LiCl was more effective than G-CSF in preserving RARalpha pools and synergized with ATRA more strongly than G-CSF. These findings suggested that the prevention of RARalpha protein loss by G-CSF or LiCl in ATRA-treated cells functioned to extend the differentiation response to the retinoid and was responsible, at least in part, for the observed synergism. D(+) cells transfected with an expression plasmid containing RARalpha cDNA had a 6- to 8-fold increase in steady-state RARalpha mRNA compared with vector-transfected cells and showed a 2- to 3-fold increase in RARalpha protein. ATRA caused a reduction, but not a complete loss, of RARalpha protein in these transfectants, which were considerably more responsive than parental D(+) cells to ATRA as a single agent, supporting the concept that the protection of RARalpha pools results in a heightened differentiation response to ATRA.
Finch
R A
RA
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Li
J
J
Chou
T C
TC
Sartorelli
A C
AC
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D018021:Lithium Chloride