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Investigation of the Effects of Heat Shock and Agents Which Induce a Heat Shock Response on the Induction of Differentiation of HL-60 Cells¹

Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, UK

A heat shock of 42.5–43.5°C for 1 h applied to HL-60 promyelocytic leukemia cells induced the appearance of between 13 and 34% (n = 6) of cells which showed characteristics of mature metamyelocytes/granulocytes. This is the first time a physical agent has been shown to induce the differentiation of this leukemic cell line. The treatment of HL-60 cells with a variety of agents which have been documented to stress cells and induce thermotolerance or a heat shock-like response also induced granulocyte-like differentiation: continuous treatment for 4 days with ethanol (213 mM), sodium arsenite (6 µM), cadmium sulfate (60 µM), lidocaine (3 mM), and procaine (5 mM) induced 73, 54, 14, 54, and 55% of cells, respectively, to reduce the dye nitro blue tetrazolium. They were also capable of the phagocytosis of yeast particles. Examination of differentiated cells showed that those treated with ethanol, arsenite, lidocaine, and procaine also expressed nonspecific esterase activity, typical of monocytes, but did not adhere to plastic and had a cellular and nuclear morphology consistent with differentiation to metamyelocytes. Analysis of protein synthesis of HL-60 cells treated with 170 mM N-methylformamide, by the pulse labeling of cells for 2 h with [¹⁴C]leucine at various times, showed that the constitutive synthesis of both the M_r 90,000 and 70,000 heat shock proteins fell substantially after 2 h of exposure to N-methylformamide. When HL-60 cells were incubated with 1 M N-methylformamide, a toxic concentration of this agent, or were heat shocked, the synthesis of both the M_r 70,000 and M_r 90,000 proteins was induced. We propose that changes in heat shock protein synthesis may be an important element of the induction of differentiation of HL-60 cells, particularly as these proteins have recently been shown to regulate the stability of oncogene proteins, such as myc (Lüscher, B., and Eisenman, R. N., Mol. Cell Biol., 8: 2504–2512, 1988).

¹ Supported by Grant SP1518 from the Cancer Research Campaign. Parts of this work have been reported elsewhere in abstract form (1).

² Recipient of a Science and Engineering Research Council Research Studentship. Present address: Department of Pathology, University of Cambridge, England.

³ To whom correspondence should be addressed.

Received 1/20/88. Revised 8/ 2/88. Accepted 9/ 1/88.

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