Inhibition of c-myc expression in human promyelocytic leukemia and colon adenocarcinoma cells by 6-thioguanine.
A rapid decrease in expression of the oncogene c-myc has been associated with the induction of differentiation of HL-60 human leukemia cells. In this manner, the treatment of a hypoxanthine phosphoribosyltransferase (HPRT)-deficient HL-60 variant (HL-60/var) with 6-thioguanine (TG) was accompanied by lower c-myc mRNA levels. This occurred in the absence of 6-thioguanosine 5'-monophosphate (TGMP) synthesis and without alterations in cellular nucleotide pool sizes. Paradoxically, inhibition of c-myc expression in the wild type HL-60 (HL-60/wt) cell, which is only weakly induced to differentiate by TG, was 5-fold more sensitive to the thiopurine (IC50 = 35 microM). Furthermore, inosine, which blocks the formation of TGMP and enhances the extent of differentiation of HL-60/wt cells, decreased the sensitivity of c-myc expression in the HL-60/wt to TG. These actions of TG and inosine on c-myc were also observed in the human colon carcinoma cell line COLO 320, further dissociating some of the effects of TG on c-myc expression from granylocytic differentiation. The hematopoietic granulocyte-macrophage colony stimulating factor (GM-CSF) elevated c-myc expression and antagonized the actions of TG on c-myc in the HL-60 cells. GM-CSF more readily antagonized the inhibitory action of TG in the HL-60/var cell line when compared to the HL-60/wt cells, restoring c-myc levels to that of the untreated controls. Hence, TG inhibited c-myc expression by two distinct mechanisms in cells which express high levels of the oncogene: a TGMP-dependent, differentiation-independent process with an IC50 of 35 microM, and a TGMP-independent action with an IC50 of 175 microM that was associated with induction of differentiation and was reversed more readily by GM-CSF.
Schwartz
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EL
Department of Oncology, Albert Einstein Cancer Center, Bronx, NY.
Chamberlin
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Brechbühl
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AB
D000230:Adenocarcinoma / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011519:Proto-Oncogenes; D012313:RNA / Q000032:analysis; D012265:Ribonucleotides / Q000032:analysis; D013866:Thioguanine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D012265:Ribonucleotides; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013866:Thioguanine