Thyroid Hormone Regulation of Apoptosis Induced by Retinoic Acid in Promyeloleukemic HL-60 Cells: Studies with Retinoic Acid Receptor-Specific and Retinoid × Receptor-Specific Ligands

Abstract

3,5,3′-Triiodo-L-thyronine (T₃) potentiates apoptosis during the all-trans-retinoic acid-induced differentiation of promyeloleukemic HL-60 cells. We examined whether the retinoid receptor-specific thyroid hormone action is present during differentiation of HL-60 cells in this study. We used two distinct retinoid receptor agonists. T₃ potentiates G₁ arrest induced by Am80, a retinoic acid receptor (RAR)-specific agonist, but had no effect on G₁ arrest induced by HX600, a retinoid × receptor (RXR)-specific agonist. Am80 alone induces the apoptosis, and T₃ enhances it. Although HX600 alone fails to increase the apoptotic fraction, T₃ enables the compounds to induce apoptosis. Am80-induced expression of CD11b, a marker for the differentiation, is enhanced by T₃. However, T₃ or HX600 or both do not affect the expression of CD11b. T₃ does not alter the amount of mRNAs of various members of the bcl-2 family. T₃, however, enhances the Am80-induced expression of bfl-1 and suppression of bcl-2. In contrast, T₃ does not alter either bfl-1 and bcl-2 expression in the presence of HX600. Our observations suggest that cooperative action of T₃ with an RXR-specific ligand is different from that with an RAR ligand in cellular apoptotic regulation and that thyroid hormone may be available as a chemotherapeutic agent in acute leukemia.