Roux Jérémie, Hafner Marc, Bandara Samuel, Sims Joshua J, Hudson Hannah, Chai Diana, Sorger Peter K
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Merrimack Pharmaceuticals, Cambridge, MA, USA.
Mol Syst Biol. 2015 May 7;11(5):803. doi: 10.15252/msb.20145584.
When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re-exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell-to-cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c-FLIP and Bcl-2), providing new insight into the control of cell fate by opposing pro-death and pro-survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists.
当细胞暴露于诸如肿瘤坏死因子相关凋亡诱导配体（TRAIL）等死亡配体时，一部分细胞会发生凋亡，而另一部分细胞则存活下来；如果存活的细胞再次暴露于TRAIL，会再次观察到部分杀伤现象。即使在饱和浓度下，针对TRAIL受体的治疗性抗体也会导致部分杀伤，从而限制了它们的有效性。部分杀伤源于蛋白质水平的细胞间波动（外在噪声），但这如何导致生与死之间清晰的分歧仍不清楚。在本文中，我们确定了起始半胱天冬酶激活的速率和时间阈值，该阈值区分了存活的细胞和死亡的细胞；通过绘制这个阈值，我们可以预测单独或与硼替佐米等致敏药物联合使用天然和合成激动剂时细胞的部分杀伤情况。该阈值的现象学模型还量化了两个抗性基因（c-FLIP和Bcl-2）的贡献，为通过对抗促死亡和促存活蛋白来控制细胞命运提供了新的见解，并提出了评估治疗性TRAIL受体激动剂疗效的新标准。
