Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs
Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs
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DOI：
10.1038/sj.onc.1203078
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发表时间：
1999-08-26
期刊：
影响因子：
8
通讯作者：
Roninson, IB
中科院分区：
文献类型：
--
作者：
Chang, BD;Xuan, YZ;Roninson, IB
人类肿瘤细胞系暴露于中等剂量的抗癌剂会诱导终末增殖停滞，并伴有类似于正常细胞衰老的形态和酶促变化。我们研究了 p53 和 p21(waf1/cip1) 在药物处理的肿瘤细胞中诱导这种反应中的作用。阿霉素治疗可诱导野生型 HCT116 结肠癌细胞出现衰老样表型 (SLP) 及其相关的终末生长停滞；在 p53 或 p21 纯合敲除的 HCT116 系中，这种反应强烈降低，但并未消除，用 p53 基因抑制剂转导 HT1080 纤维肉瘤细胞也减少了 SLP 的诱导，并增加了药物诱导的有丝分裂细胞死亡。为了确定药物刺激的 p21 表达是否导致衰老样生长停滞，我们从诱导型启动子表达了不同水平的 p21，而高水平p21 的过表达足以在 HT1080 细胞中诱导 SLP，而阿霉素处理的细胞中 p21 的表达水平只能解释阿霉素诱导的 SLP 的一小部分。我们的结果表明，p53 和 p21 充当衰老样终末增殖停滞的正调节因子，但它们的功能对于肿瘤细胞中的这种治疗反应既不充分也不是绝对必需的。
Exposure of human tumor cell lines to moderate doses of anticancer agents induces terminal proliferation arrest accompanied by morphologic and enzymatic changes that resemble senescence of normal cells, We have investigated the role of p53 and p21(waf1/cip1) in the induction of this response in drug-treated tumor cells. Doxorubicin treatment induced the senescence-like phenotype (SLP) and its associated terminal growth arrest in wild-type HCT116 colon carcinoma cells; this response was strongly decreased but not abolished in HCT116 lines with homozygous knockout of p53 or p21, Transduction of HT1080 fibrosarcoma cells with a genetic inhibitor of p53 also decreased the induction of SLP and increased drug-induced mitotic cell death, To determine if drug-stimulated p21 expression was responsible for senescence-like growth arrest, we have expressed different levels of p21 from an inducible promoter, While high-level overexpression of p21 was sufficient to induce SLP in HT1080 cells, the levels of p21 expressed in doxorubicin-treated cells could account for only a fraction of doxorubicin-induced SLP, Our results indicate that p53 and p21 act as positive regulators of senescence-like terminal proliferation arrest, but their function is neither sufficient nor absolutely required for this treatment response in tumor cells.