Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
J Theor Biol. 2019 Dec 21;483:109992. doi: 10.1016/j.jtbi.2019.109992. Epub 2019 Sep 4.
Signal integration has a crucial role in the cell fate decision and dysregulation of the cellular signaling pathways is a primary characteristic of cancer. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels, including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein (Le Chatelier's principle). 2-Components like Phosphatidic Acid (PA) further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes in the cancer cells, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier's principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. This model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.
信号整合在细胞命运决定中起着至关重要的作用，细胞信号通路的失调是癌症的主要特征。作为信号整合器，mTOR 表现出复杂的动态行为，这种行为决定了不同细胞过程水平下的细胞命运，包括细胞周期进程、细胞存活、细胞死亡、代谢重编程和衰老。细胞对雷帕霉素的复杂反应动力学归因于其对 mTORC1 和 mTORC2 的时间依赖性抑制作用不同，mTORC1 和 mTORC2 是 mTOR 的两个主要复合物。此前，针对这种现象提出了两种解释：1.雷帕霉素不会直接抑制 mTORC2，而是通过隔离游离的 mTOR 蛋白来阻止 mTORC2 的形成（勒沙特列原理）。2.与 mTORC1 相比，像磷酸脂酸（PA）等成分进一步稳定了 mTORC2。为了理解雷帕霉素在癌细胞中差异抑制 mTOR 复合物的机制，我们提出了一种基于第一种解释（即勒沙特列原理）的雷帕霉素作用模式的数学模型。将 mTORC1 和 mTORC2 中各成分之间的相互作用转化为数学模型，揭示了不同剂量雷帕霉素和不同时间间隔雷帕霉素处理的雷帕霉素作用动力学。该模型表明，雷帕霉素对 mTORC1 的作用比对 mTORC2 的作用更强，这仅仅是因为它与游离的 mTOR 和 mTORC1 直接相互作用，而不是与 mTORC2 相互作用，而无需考虑可能进一步稳定 mTORC2 的其他成分。根据我们的结果，即使与 mTORC1 相比，mTORC2 不太稳定，它也可能受到雷帕霉素的抑制作用较小。
