p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells.
p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells.
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DOI：
10.1128/mcb.00747-15
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发表时间：
2016-02-01
影响因子：
5.3
通讯作者：
Saab R
中科院分区：
文献类型：
--
作者：
Harajly M;Zalzali H;Nawaz Z;Ghayad SE;Ghamloush F;Basma H;Zainedin S;Rabeh W;Jabbour M;Tawil A;Badro DA;Evan GI;Saab R
p53的恢复已被认为是一种治疗肿瘤的方法。然而，在肿瘤进展过程中，p53恢复的时间与其疗效的关系尚不清楚。我们现在表明，p53在小鼠恶性前增殖松果体病变中的恢复会导致细胞衰老，而p53在侵袭性松果体肿瘤中的恢复则不会。p53恢复的有效性不依赖于p19Arf的表达，但与Mdm2的表达呈负相关。在肿瘤细胞中，当与dna损伤疗法或p53- mdm2相互作用抑制剂nutlin配对时，p53恢复是有效的。有趣的是，衰老后p53的失活导致重新进入细胞周期和肿瘤的快速进展。一组人类幕上原始神经外胚层肿瘤（sPNET）的评估显示p53通路活性低。综上所述，这些数据表明p53通路的恢复在恶性肿瘤前期和侵袭性松果体肿瘤中具有不同的作用，并且p53的激活需要持续维持，因为当p53再次丢失时，随着肿瘤的侵袭性生长，衰老的逆转会迅速发生。最后，p53恢复方法可能值得在sPNET中探索，其中p53基因是完整的，但在大多数被检查的肿瘤中该途径是不活跃的。
The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19Arf expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.