Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF-7 breast tumor cells following acute exposure to doxorubicin
Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF-7 breast tumor cells following acute exposure to doxorubicin
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DOI：
10.1016/0006-2952(96)00050-0
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发表时间：
1996-04-12
影响因子：
5.8
通讯作者：
Gewirtz, DA
中科院分区：
文献类型：
--
作者：
Fornari, FA;Jarvis, WD;Gewirtz, DA
在MCF-7人野兽腺癌细胞系中，急性暴露于1亩M阿霉素对细胞增殖的抑制作用类似于75%。细胞周期分析表明，在24小时内，G(2)/M期细胞比例增加3倍以上，S期细胞减少50%。除了生长停滞，在72KR之后，活细胞数量也有类似的40%的减少。细胞暴露于阿霉素后立即进行的低分子DNA凝胶电泳法未能显示出与细胞凋亡相关的“梯状”寡核体图谱。在细胞暴露于1亩M阿霉素后，荧光分光光度法在72小时间隔内证实细胞内没有DNA片段或片段DNA释放到孵育液中。此外，在此期间，没有证据表明与细胞凋亡有关的形态特征。急性暴露于1亩M阿霉素也会导致c-myc基因表达的一过性增加(在第一个小时内)，然后在2-4小时内下降到对照水平的70%。C-myc基因表达水平的降低具有浓度依赖性，并与生长停滞(以及DNA合成的抑制)密切相关。这些发现(以及类似的报告表明，在MCF-7细胞中，VM-26和m-AMSA降低了c-myc表达和抑制生长之间的对应关系)表明，c-myc表达下调可能反映了调控过程中的扰动，导致暴露于拓扑异构酶II抑制剂的MCF-7细胞生长停滞。
In the MCF-7 human beast adenocarcinoma cell line, acute exposure to 1 mu M doxorubicin inhibited cell proliferation by similar to 75%. Analysis of cell cycle distribution indicated that within 24 hr, the G(2)/M fraction increased more than 3-fold and the S-phase population declined by >50%. In addition to growth arrest, there was an similar to 40% reduction in the viable cell population after 72 kr. Gel electrophoretic resolution of low molecular weight DNA immediately after exposure of cells to doxorubicin failed to demonstrate ''laddered'' oligonucleosomal profiles associated with apoptosis. The absence of intracellular DNA fragments or release of fragmented DNA into the incubation medium was confirmed by spectrofluorophotometry over a 72 hr interval following exposure of cells to 1 mu M doxorubicin. In addition, there was no evidence of the morphological features associated with apoptosis during this period. Acute exposure to 1 mu M doxorubicin also produced a transient increase in c-myc message expression (within the first hour) followed by a decline to 70% of control levels within 2-4 hr. The reduction in c-myc mRNA levels was concentration dependent and corresponded closely with growth arrest (as well as with inhibition of DNA synthesis). These findings (as well as similar reports demonstrating a correspondence between reduced c-myc expression and growth inhibition by VM-26 and m-AMSA in MCF-7 cells) suggest that the down-regulation of c-myc expression may reflect perturbations in regulatory processes contributing to growth arrest in MCF-7 cells exposed to to topoisomerase II inhibitors.