Differential effect of 6-ethylmercaptopurine on c-myc expression in wild-type and HGPRT-deficient HL-60 cells |
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| Authors: | Bernard T. French Dawn E. Patrick Michael R. Grever Ronald W. Trewyn |
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| Affiliation: | (1) Comprehensive Cancer Center and Department of Physiological Chemistry, The Ohio State University, 410 W 12th Avenue, 43210 Columbus, Ohio, USA;(2) Present address: Division of Cancer Treatment, NCl, 9000 Rockville Pike, 20892 Bethesda, MD, USA |
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| Abstract: | Summary A variety of compounds inhibit the growth and induce differentiation of human promyelocytic leukemia (HL-60) cells. HL-60 subclones that lack the purine salvage enzyme hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) can also be induced to differentiate with purine analogs. Mechanisms by which purine analogs induce differentiation offer unique possibilities for cancer chemotherapy. We have studied the effect of the purine analog 6-ethylmercaptopurine (e6MP) on the growth and induction of differentiation in both wild-type and HGPRT-deficient HL-60 cells. We have previously shown that e6MP inhibits cell growth in both wild-type and HGPRT-deficient HL-60 cells without activation through salvage pathways [8]. In this report we evaluate the effect of e6MP on c-myc mRNA expression. c-Myc mRNA, which is amplified in HL-60 cells, has been shown to play a role in the induction of granulocytic differentiation in HL-60 cells. e6MP transiently down-regulates c-myc mRNA in wild-type cells but has no efect on c-myc mRNA expression in HGPRT-deficient HL-60 cells. Despite the differential effects of e6MP on c-myc mRNA, both wild-type and HGPRT-deficient HL-60 cells appear to engage in terminal differentiation. The morphological changes and nonspecific esterase activity induced by e6MP suggest differentiation down the monocytic pathway. However, early monocytic markers such as the rapid induction of c-fos and the stabilization of c-fms mRNA are not observed. In addition, e6MP inhibits TPA-induced monocytic/macrophage differentiation as characterized by stabilization of c-fms mRNA and cellular adherence.Abbreviations e6MP 6-ethylmercaptopurine - 6-TG 6-thioguanine - MP 6-mercaptopurine - 8-AzaG 8-azaguanine - FBS fetal bovine serum - HGPRT hypoxanthine-guanine phosphoribosyltransferaseSupported by grant CH-396 (R.W.T., M.R.G.) from the American Cancer Society, developmental grant IN16Y (B.T.F.) from the American Cancer Society, and grant P30-CA-16058-15 [OSUCCC] from the National Cancer Institute, Department of Health and Human Services |
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