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Phorbol Ester-induced Macrophage-like Differentiation of Human Promyelocytic Leukemia (HL-60) Cells Occurs Independently of Transferrin Availability¹

Division of Biochemistry, Department of Cellular and Molecular Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom

Human promyelocytic leukemia (HL-60) cells can be induced to differentiate into macrophage-like cells by the tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). Addition of this agent to HL-60 cells causes a rapid internalization of surface transferrin receptor, followed by long-term receptor down-regulation at the level of gene expression. These effects precede the inhibition of proliferation and the acquisition of differentiation markers, and it has been suggested that transferrin receptor down-regulation may play a mediating role in these later events. Here we show that HL-60 cells will grow indefinitely in serum-free medium supplemented with either 5 µg ml^-1 transferrin or 300 µM ferric citrate and that TPA inhibits cell proliferation (assayed by cell density and rate of thymidine incorporation) and induces macrophage-like differentiation (assayed by induction of cell adhesion and increased nonspecific esterase activity) with identical dose curves in both media. Furthermore, a neutralizing anti-transferrin antibody completely inhibits transferrin-dependent cell proliferation but has no effect on differentiation in the presence or absence of transferrin. We conclude that TPA-induced down-regulation of transferrin binding and internalization does not mediate the subsequent growth arrest and differentiation of HL-60 cells.

¹ This research was funded by Glaxo Group Research, Greenford, UK, the Cancer Research Campaign, and the Leukaemia Research Fund.

² To whom requests for reprints should be addressed.

Received 3/12/90. Accepted 8/13/90.