COMPARATIVE RESPONSIVENESS OF HL-60, HL-60R, AND HL-60R(-CIS-RETINOICACID, AND SODIUM-BUTYRATE() (LRARSN)CELLS TO RETINOIC ACID, CALCITRIOL, 9)

In HL-60 cells, retinoic acid (RA) and 9 cis-RA induce granulocytic di fferentiation, and calcitriol and sodium butyrate induce monocytic dif ferentiation. To study the role of retinoid resistance on the response to these agents, we investigated their effects in HL-60 cells, retino id-resistant HL-60R cells, and HL-60R(+) cells in which retinoid sensi tivity has been restored. In HL-60 cells, cathepsin D (ctsd) mRNA leve ls are increased by these agents and by cholera toxin after pretreatme nt with each agent. Calcitriol, 9 cis-RA, and sodium butyrate increase interleukin-8 (IL-8) mRNA expression, and pretreatment with these age nts or RA potentiates the stimulation of IL-8 by phorbol ester (TPA). Pretreatment of HL-60 cells with all of the agents confers inducibilit y of cathepsin L (ctsI) mRNA by TPA in previously unresponsive cells. In HL-60R cells, none of the agents alone or in combination significan tly enhances the expression of the ctsd, IL-8, or ctsI mRNAs. Retinoid stimulation (either alone or in combination with the other agents) of the three mRNAs is partially restored in the HL-60R(+) cells. Calcitr iol does not alter the expression of any of these mRNAs, and only the stimulation of IL-8 mRNA by sodium butyrate is recovered. Treatment wi th all of the agents inhibits proliferation and stimulates differentia tion of the HL-60 cells. RA and calcitriol are unable to inhibit proli feration of the HL-60R cells, whereas only calcitriol fails to inhibit proliferation of the HL-60R(+) cells. None of the agents induces diff erentiation in either the HL-60R or HL-60R(+) cells. Therefore, the mu tation of the RA receptor ct is insufficient to account for the altere d responses of the HL-60R cells, and there are likely defects in other signaling pathways in these cells. These cells may prove useful in ex amining the mechanism of cross-resistance between various differentiat ing agents. (C) 1995 by The American Society of Hematology.