Functional interactions between bile acids, all-trans retinoic acid, and 1,25-dihydroxy-vitamin D-3 on monocytic differentiation and myeloblastin gene down-regulation in HL60 and THP-1 human leukemia cells

Bile acids were shown previously to inhibit proliferation and to induce mon ocytic differentiation in HL60 human acute promyelocytic leukemia cells (A. Zimber et al,, Int. J. Cancer, 59: 71-77, 1994), In this report, we hypoth esized that bile acids may exert a positive cooperativity with two known in ducers of leukemic cell differentiation, all-trans retinoic acid and 1,25(O H)(2)-vitamin D-3. Our results provide evidence that bile acids induced the monocytic differentiation of HL60 and THP-1 human leukemia cells exposed t o ineffective concentrations of these inducers. The protein kinase C (PKC) inhibitors H-7 (10 and 20 mu M) and staurosporine (5 and 20 nM) modulated t he effects of bile acids on HL60 cell differentiation. Most interestingly, bile acids are shown herein to down-regulate the expression of the serine p rotease myeloblastin gene involved in the differentiation of myeloid hemato poietic cells. In agreement with the recent identification of nuclear receptors for bile a cids, our data suggest that functional interactions between nuclear bile ac id signaling pathways, PKC, and nuclear receptors for retinoic acid and vit amin D-3 are involved in the down-regulation of the myeloblastin gene and t he induction of cell differentiation in human leukemic cells.