Transcriptional down-regulation of c-myc expression in the MCF-7 breast tumor cell line by the topoisomerase II inhibitor, VM-26.
In the MCF-7 human breast tumor cell line, the topoisomerase II inhibitor, VM-26, produces a concentration dependent reduction in expression of the oncogene c-myc which parallels growth inhibition. Down-regulation of c-myc expression was examined at transcriptional and post-transcriptional levels. VM-26, at 10 microM, produced a reduction in the transcription rate of both sense and antisense strands of c-myc as determined by nuclear run-off analysis. In contrast, in the presence of the RNA synthesis inhibitor, actinomycin D, VM-26 failed to alter the half-life of the c-myc message. The capacity of VM-26 to reduce c-myc expression was not abrogated in cells pretreated with the protein synthesis inhibitor, cycloheximide (despite superinduction of c-myc expression in both control and VM-26 treated cells); this observation suggests that de novo protein synthesis may not be required to mediate the effects of VM-26 on steady state c-myc transcript levels. An extended analysis of the time course of c-myc expression demonstrated that the decline of steady state c-myc mRNA levels induced by VM-26 was biphasic, 6 h after the initial reduction in c-myc expression to approx. 30% of control levels, c-myc levels rebounded to 70% of control; after 24 h, c-myc expression declined gradually and remained at depressed levels (40% of control) at 48 and 72 h. These observations suggest that the initial transient reduction in c-myc expression associated with inhibition of transcription may represent a component of an early signalling pathway leading to growth arrest in MCF-7 breast tumor cells exposed to VM-26.
Orr
M S
MS
Department of Pharmacology/Toxicology, Medical College of Virginia, Richmond 23298, USA.
Fornari
F A
FA
Randolph
J K
JK
Gewirtz
D A
DA
D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line / Q000187:drug effects; D004247:DNA / Q000302:isolation & purification; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D013713:Teniposide / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects
D016271:Proto-Oncogene Proteins c-myc; D059005:Topoisomerase II Inhibitors; D004247:DNA; D013713:Teniposide