Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0035, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, 252-8520, Japan.
Sci Rep. 2011;1:144. doi: 10.1038/srep00144. Epub 2011 Nov 7.
The tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis in malignant cells, while leaving other cells mostly unharmed. However, several carcinomas remain resistant to TRAIL. To investigate the resistance mechanisms in TRAIL-stimulated human fibrosarcoma (HT1080) cells, we developed a computational model to analyze the temporal activation profiles of cell survival (IκB, JNK, p38) and apoptotic (caspase-8 and -3) molecules in wildtype and several (FADD, RIP1, TRAF2 and caspase-8) knock-down conditions. Based on perturbation-response approach utilizing the law of information (signaling flux) conservation, we derived response rules for population-level average cell response. From this approach, i) a FADD-independent pathway to activate p38 and JNK, ii) a crosstalk between RIP1 and p38, and iii) a crosstalk between p62 and JNK are predicted. Notably, subsequent simulations suggest that targeting a novel molecule at p62/sequestosome-1 junction will optimize apoptosis through signaling flux redistribution. This study offers a valuable prospective to sensitive TRAIL-based therapy.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导恶性细胞凋亡，而使其他细胞基本不受伤害。然而，一些癌仍然对 TRAIL 具有抗性。为了研究 TRAIL 刺激的人纤维肉瘤（HT1080）细胞中的抗性机制，我们开发了一种计算模型来分析细胞存活（IκB、JNK、p38）和凋亡（caspase-8 和 -3）分子在野生型和几种（FADD、RIP1、TRAF2 和 caspase-8）敲低条件下的时间激活谱。基于利用信息（信号流）守恒定律的扰动向量响应方法，我们推导出了群体平均细胞响应的响应规则。从该方法中，i）预测了一种不依赖于 FADD 的途径来激活 p38 和 JNK，ii）RIP1 和 p38 之间的串扰，以及 iii）p62 和 JNK 之间的串扰。值得注意的是，随后的模拟表明，靶向 p62/自噬体-1 结合处的新型分子将通过信号流再分配优化细胞凋亡。本研究为敏感的 TRAIL 为基础的治疗提供了有价值的前景。
