Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells
Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells
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DOI：
10.1158/1541-7786.mcr-09-0144
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发表时间：
2009-09-01
影响因子：
5.2
通讯作者：
Vassilev, Lyubomir T.
中科院分区：
文献类型：
--
作者：
Huang, Baoying;Deo, Dayanand;Vassilev, Lyubomir T.
细胞衰老是一种压力诱导的不可逆转的生长停滞状态，被认为是癌症发展的障碍。P53肿瘤抑制因子是衰老的重要介质，最近的体内研究表明，P53诱导的衰老可能有助于免疫系统对肿瘤的清除。最近开发的MDM2拮抗剂Nutlins是有效的P53激活剂和强大的抗肿瘤药物，在具有功能性凋亡途径的细胞中。然而，它们只阻止p53凋亡信号受损的癌细胞的细胞周期进程。我们使用Nutlin-3a作为选择性探针，利用八个上皮癌细胞株和原代上皮细胞来研究P53激活在衰老中的作用。我们的结果表明，MDM2拮抗剂可以在所有受试细胞系中诱导类衰老状态，但这种状态是可逆的，当药物去除和P53控制正常化后，细胞恢复增殖。先前在成纤维细胞衰老过程中参与基因沉默的视网膜母细胞瘤家族成员(pRb、p107和p130)在Nutlin诱导的衰老样表型细胞中表达下调，提示其可逆性机制。因此，选择性地激活P53通路不足以在体外诱导上皮细胞的真正衰老。然而，在具有Nutlin诱导的衰老样表型的癌细胞中，几种炎性细胞因子的表达增加，这表明P53激活疗法可能在体内受益。(摩尔癌症研究2009；7(9)：1497-509)
Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies. (Mol Cancer Res 2009;7(9):1497-509)