POSSIBLE INVOLVEMENT OF CALCINEURIN IN RETINOIC ACID-INDUCED INHIBITION OF LEUKEMIC HL-60 CELL-PROLIFERATION

Differentiation of leukemic HL-60 cells by all trans-retinoic acid (AT RA) resulted in a reduced rate of growth. Cyclosporin A and FK506, at concentrations that inhibited calcineurin activity, abrogated the ATRA -induced inhibition of HL-60 cell growth but these immunosuppressants had no effect on the ATRA-induced granulocytic differentiation. Treatm ent with 1 mu M ATRA led to a progressive increase in calcineurin phos phatase activity of HL-60 cells; the increase in this activity appeare d to parallel the functional change of HL-60 cells during granulocytic differentiation. Increase in calcineurin activity was concordant with the increased expressions of calcineurin A and calcineurin B subunit proteins. The FKBP12 expression increased during ATRA-induced differen tiation and expression of cyclophilin A remained unchanged. We propose that the increased expression of calcineurin is involved in the ATRA- induced inhibition of HL-60 cell proliferation, as in the case with 1, 25 alpha-dihydroxyvitamin D-3.