TY - JOUR
T1 - Inhibition of c-myc expression in human promyelocytic leukemia and colon adenocarcinoma cells by 6-thioguanine
AU - Schwartz, Edward L.
AU - Chamberlin, Helena
AU - Brechbühl, Anna Barbara
N1 - Funding Information:
Acknowledgements-We thank Laura Nilson, Michael Pizzillo and Ivan Ramirez for their technical assistance, and Dr. Robert Gallagher for providing the TG-resistant HL-60 cells. This work was supported by a grant from the Mathers Foundation.
PY - 1990/12/1
Y1 - 1990/12/1
N2 - 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 μM). 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 μM, and a TGMP-independent action with an ic50 of 175 μM that was associated with induction of differentiation and was reversed more readily by GM-CSF.
AB - 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 μM). 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 μM, and a TGMP-independent action with an ic50 of 175 μM that was associated with induction of differentiation and was reversed more readily by GM-CSF.
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U2 - 10.1016/0006-2952(90)90085-Y
DO - 10.1016/0006-2952(90)90085-Y
M3 - Article
C2 - 1702632
AN - SCOPUS:0025684590
SN - 0006-2952
VL - 40
SP - 2449
EP - 2455
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -