Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent
Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent
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DOI：
10.1073/pnas.012602599
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发表时间：
2002-01-08
影响因子：
11.1
通讯作者：
Roninson, IB
中科院分区：
文献类型：
--
作者：
Chang, BD;Swift, ME;Roninson, IB
化疗或放疗对所有的肿瘤细胞并不总是具有细胞毒性。一些在治疗中存活的细胞恢复并恢复增殖，而另一些细胞则经历永久性生长停滞。为了了解治疗诱导的终末生长停滞的性质，将结肠癌细胞暴露于阿霉素，并将存活的细胞分离成增殖和生长停滞的群体。只有生长停滞的细胞表现出细胞衰老的表型标记，未能形成集落。通过cDNA微阵列杂交和逆转录-PCR比较药物处理的细胞衰老和增殖组分之间的基因表达。药物诱导的衰老与细胞增殖相关基因的抑制和多种细胞内和分泌的生长抑制剂的共诱导有关。几个肿瘤抑制因子和其他基因在癌发生过程中下调，在衰老的肿瘤细胞中上调。大多数生长抑制剂的诱导被延迟，但没有取消与纯合子敲除p53的细胞，在协议中只有有限的p53药物诱导的终端生长停滞的依赖。另一方面，衰老细胞过表达分泌的蛋白质与抗凋亡，促有丝分裂，血管生成的活动，表明药物诱导的衰老与旁分泌肿瘤促进作用。在p21（Waf 1/Cip 1/Sdi 1）缺陷的细胞中，大约三分之一的基因在衰老细胞中上调，几乎所有下调的基因表现出减少或延迟的变化，表明p21是p53对基因表达影响的主要介质。阐明肿瘤细胞中发生药物诱导衰老的分子变化，提示了在癌症治疗中对这种抗增殖反应进行诊断和治疗调节的潜在策略。
Treatment with chemotherapy or radiation is not invariably cytotoxic to all tumor cells. Some of the cells that survive treatment recover and resume proliferation, whereas others undergo permanent growth arrest. To understand the nature of treatment-induced terminal growth arrest, colon carcinoma cells were exposed to doxorubicin, and surviving cells were separated into proliferating and growth-arrested populations. Only growth-arrested cells displayed phenotypic markers of cell senescence and failed to form colonies. Gene expression was compared between senescent and proliferating fractions of drug-treated cells by using cDNA microarray hybridization and reverse transcription-PCR. Drug-induced senescence was associated with inhibition of genes involved in cell proliferation and with coinduction of multiple intracellular and secreted growth inhibitors. Several tumor suppressors and other genes that are down-regulated in carcinogenesis were up-regulated in senescent tumor cells. Induction of most growth inhibitors was delayed but not abolished in cells with homozygous knockout of p53, in agreement with only limited p53 dependence of drug-induced terminal growth arrest. On the other hand, senescent cells overexpressed secreted proteins with antiapoptotic, mitogenic, and angiogenic activities, suggesting that drug-induced senescence is associated with paracrine tumor-promoting effects. About one-third of the genes up-regulated in senescent cells and almost all of the down-regulated genes showed decreased or delayed changes in p21(Waf1/Cip1/Sdi1)-deficient cells, indicating that p21 is a major mediator of the effects of p53 on gene expression. Elucidation of molecular changes in tumor cells that undergo drug-induced senescence suggests potential strategies for diagnostics and therapeutic modulation of this anti proliferative response in cancer treatment.