p53动力学中的细胞间差异导致部分杀伤。
Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing.
作者信息
Paek Andrew L, Liu Julia C, Loewer Alexander, Forrester William C, Lahav Galit
机构信息
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
出版信息
Cell. 2016 Apr 21;165(3):631-42. doi: 10.1016/j.cell.2016.03.025. Epub 2016 Apr 7.
Many chemotherapeutic drugs kill only a fraction of cancer cells, limiting their efficacy. We used live-cell imaging to investigate the role of p53 dynamics in fractional killing of colon cancer cells in response to chemotherapy. We found that both surviving and dying cells reach similar levels of p53, indicating that cell death is not determined by a fixed p53 threshold. Instead, a cell's probability of death depends on the time and levels of p53. Cells must reach a threshold level of p53 to execute apoptosis, and this threshold increases with time. The increase in p53 apoptotic threshold is due to drug-dependent induction of anti-apoptotic genes, predominantly in the inhibitors of apoptosis (IAP) family. Our study underlines the importance of measuring the dynamics of key players in response to chemotherapy to determine mechanisms of resistance and optimize the timing of combination therapy.
许多化疗药物只能杀死一小部分癌细胞，从而限制了它们的疗效。我们利用活细胞成像技术来研究p53动态变化在结肠癌细胞对化疗的部分杀伤反应中的作用。我们发现，存活细胞和死亡细胞的p53水平相似，这表明细胞死亡并非由固定的p53阈值决定。相反，细胞的死亡概率取决于p53的时间和水平。细胞必须达到p53的阈值水平才能执行凋亡，并且这个阈值会随着时间增加。p53凋亡阈值的增加是由于抗凋亡基因的药物依赖性诱导，主要是凋亡抑制蛋白（IAP）家族中的基因。我们的研究强调了测量关键因子对化疗反应的动态变化以确定耐药机制并优化联合治疗时机的重要性。
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