A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
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DOI：
10.1172/jci40535
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
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作者：
Alimonti, Andrea;Nardella, Caterina;Pandolfi, Pier Paolo
不可逆的细胞生长停滞，这一被称为细胞衰老的过程，正逐渐成为一种内在的肿瘤抑制机制。癌基因诱导的衰老被认为总是先出现细胞过度增殖、异常复制以及DNA损伤检查点反应（DDR）的激活，这使得对这一过程进行治疗性增强不适用于癌症治疗。我们先前在一个前列腺癌小鼠模型中证明，10号染色体上缺失的肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）失活会引发一种对抗肿瘤发生的衰老反应。在此，我们表明PTEN缺失诱导的细胞衰老（PICS）代表了一种不同于癌基因诱导的衰老反应，并且可作为癌症治疗的靶点。利用小鼠胚胎成纤维细胞，我们确定在PTEN失活后，在没有细胞增殖和DDR的情况下，PICS会迅速发生。此外，我们发现PICS与p53翻译增强有关。与这些数据一致的是，我们表明在小鼠中，稳定p53的药物增强了PICS及其肿瘤抑制潜能。重要的是，我们证明了在一个人前列腺癌异种移植模型中，对PTEN的药物抑制在体内驱动衰老并抑制肿瘤发生。总之，我们的数据确定了一种在没有DNA损伤的情况下可在非增殖细胞中触发的细胞衰老类型，我们相信这将有助于开发一种用于癌症预防和治疗的“促衰老”方法。
Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss-induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a "pro-senescence" approach for cancer prevention and therapy.