Harajly Mohamad, Zalzali Hasan, Nawaz Zafar, Ghayad Sandra E, Ghamloush Farah, Basma Hussein, Zainedin Samiha, Rabeh Wissam, Jabbour Mark, Tawil Ayman, Badro Danielle A, Evan Gerard I, Saab Raya
Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
Cytogenetics and Molecular Cytogenetic Laboratory, Hamad General Hospital, Doha, Qatar.
Mol Cell Biol. 2015 Nov 23;36(3):438-51. doi: 10.1128/MCB.00747-15. Print 2016 Feb 1.
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 p19(Arf) 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.
恢复p53功能已被提议作为一种肿瘤治疗方法。然而，p53功能恢复的时机与其在肿瘤进展过程中的疗效之间的关系仍不明确。我们现在发现，在小鼠松果体癌前增殖性病变中恢复p53功能会导致细胞衰老，而在侵袭性松果体肿瘤中恢复p53功能则不会。p53功能恢复的有效性并不依赖于p19(Arf)的表达，而是与Mdm2的表达呈负相关。在肿瘤细胞中，当p53功能恢复与DNA损伤疗法或与p53-Mdm2相互作用抑制剂nutlin联合使用时，变得有效。有趣的是，衰老后p53失活会导致细胞重新进入细胞周期并使肿瘤快速进展。对一组人类幕上原始神经外胚层肿瘤（sPNET）的评估显示，p53通路活性较低。总之，这些数据表明，p53通路的恢复在松果体癌前肿瘤和侵袭性肿瘤中具有不同的作用，并且p53激活需要持续维持，因为当p53再次缺失时，随着肿瘤的快速生长，衰老会迅速逆转。最后，在p53基因完整但在大多数检测肿瘤中该通路无活性的sPNET中，恢复p53功能的方法可能值得探索。
