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Differential Effects of Long-Chain (Sphingoid) Bases on the Monocytic Differentiation of Human Leukemia (HL-60) Cells Induced by Phorbol Esters, 1,25-Dihydroxyvitamin D₃, or Ganglioside G_M3¹

Departments of Biochemistry [V. L. S., N. E. O., J. M. K., A. H. M.] and Medicine [E. E. S., E. F. W.], Emory University, Atlanta, Georgia 30322

Conditions were developed to prolong the ability of sphinganine, a potent inhibitor of protein kinase C, to block the phorbol ester-induced adherence of HL-60 cells beyond 24 h. The loss of inhibition after this time seen previously (A. H. Merrill, Jr., A. M. Sereni, V. L. Stevens, Y. A. Hannun, R. M. Bell, and J. M. Kinkade, Jr., J. Biol. Chem., 261: 12610–12615, 1986), which appeared to be due to metabolism of this long-chain base, was overcome by supplying sphinganine daily. After 4 days, phorbol myristate acetate-induced adherence was inhibited approximately 50% by sphinganine. Sphinganine significantly decreased the expression of nonspecific esterase induced by phorbol myristate acetate in the nonadherent cells, indicating that other aspects of maturation besides adherence were blocked. The effects of daily sphinganine treatments on the monocytic differentiation induced by 1,25-dihydroxyvitamin D₃ or ganglioside G_M3 were also investigated. The increases in nonspecific esterase expression, nitroblue tetrazolium reduction, and morphological maturation caused by either agent were unaffected by the long-chain base. In addition, the changes in several cell surface antigens caused by 1,25-dihydroxyvitamin D₃ were unaltered by sphinganine. Although phorbol esters, 1,25-dihydroxyvitamin D₃, and ganglioside G_M3 all induce the maturation of HL-60 cells along the monocytic lineage, the finding that sphinganine only affected the differentiation initiated by phorbol esters, in which protein kinase C clearly is a major regulator, suggests that this enzyme does not play a major role in these other pathways of differentiation.

¹ This work was supported by Grants GM33369 (A. H. M.), CA46508 (A. H. M.), and CA22294 (J. M. K.) from NIH and by the Jill Andrews Memorial Fund for Leukemia Research (E. F. W.).

² To whom requests for reprints should be addressed.

Received 9/27/88. Revised 3/ 8/89. Accepted 3/22/89.

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