Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Several anti-cancer interventions function partly by inducing malignant cells into senescence. However, because of systemic administration and lack of specificity, anti-cancer treatments are associated with premature senescence of various non-malignant cells. Therapy-induced non-malignant senescent cells can have profound detrimental pro-tumorigenic and pro-disease functions via activation of a pro-inflammatory and NF-κB-mediated secretory phenotype (SASP). Inhibitors of the cyclin-dependent kinases 4/6 (CDK4/6i) has recently shown to have potent cytostatic effects with reduced toxicities. Here, we show that CDK4/6i lead non-malignant cells to a senescent state that lacks the pro-inflammatory and NF-κB-associated SASP. Interestingly, CDK4/6i-induced senescence overexpressed a number of genes encoding for secreted proteins, which we show being dependent on p53 transcriptional activity. CDK4/6i-induced p16+ senescent cells with a p53-associated (PASP), but not NF-κB-associated (NASP), secretory phenotype do not exert detrimental and pro-tumorigenic functions, but still retain the capacity to induce paracrine senescence and undergo clearance in vivo. Our data suggest that that senescent cells with a PASP but without a NASP may be well-tolerated and may represent a less toxic outcome for cancer interventions.

中文翻译：

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药理性CDK4 / 6抑制作用可揭示衰老细胞中p53诱导的分泌表型

细胞衰老是稳定的生长停滞状态，其充当肿瘤抑制机制。几种抗癌干预措施部分通过诱导恶性细胞衰老来发挥作用。但是，由于全身给药和缺乏特异性，抗癌治疗与各种非恶性细胞的过早衰老有关。通过治疗促炎和NF-κB介导的分泌表型（SASP）的激活，治疗诱导的非恶性衰老细胞可能具有深远的有害促肿瘤作用和促疾病作用。细胞周期蛋白依赖性激酶4/6（CDK4 / 6i）的抑制剂最近显示具有有效的细胞抑制作用，且毒性降低。在这里，我们显示CDK4 / 6i导致非恶性细胞进入衰老状态，而该衰老状态缺乏促炎性和NF-κB相关的SASP。有趣的是 CDK4 / 6i诱导的衰老过表达了许多编码分泌蛋白的基因，我们证明它们依赖于p53转录活性。CDK4 / 6i诱导的具有p53关联（PASP）而非NF-κB关联（NASP），分泌表型的p16 +衰老细胞不发挥有害和促肿瘤作用，但仍保留了诱导旁分泌衰老和在体内进行清除。我们的数据表明，具有PASP但不具有NASP的衰老细胞可能具有良好的耐受性，并且对癌症干预的毒性较小。分泌表型不发挥有害和促肿瘤作用，但仍保留诱导旁分泌衰老并在体内清除的能力。我们的数据表明，具有PASP但不具有NASP的衰老细胞可能具有良好的耐受性，并且对癌症干预的毒性较小。分泌表型不发挥有害和促肿瘤作用，但仍保留诱导旁分泌衰老并在体内清除的能力。我们的数据表明，具有PASP但不具有NASP的衰老细胞可能具有良好的耐受性，并且对癌症干预的毒性较小。