Department of Physics, George Washington University, 725 21st Street NW, Washington, DC 20052, USA.
Phys Biol. 2010 Dec 22;7(4):046015. doi: 10.1088/1478-3975/7/4/046015.
Connections between cancer and metabolic diseases may consist in the complex network of interactions among a common set of biomolecules. By applying singularity and bifurcation analysis, the phenotypes constrained by the AKT signaling pathway are identified and mapped onto the parameter space, which include cancer and certain metabolic diseases. By considering physiologic properties (sensitivity, robustness and adaptivity) the AKT pathway must possess in order to efficiently sense growth factors and nutrients, the region of normal responses is located. To optimize these properties, the intracellular concentration of the AKT protein must be sufficiently high to saturate its enzymes; the strength of the positive feedback must be stronger than that of the negative feedback. The analysis illuminates the parameter space and reveals system-level mechanisms in regulating biological functions (cell growth, survival, proliferation and metabolism) and how their deregulation may lead to the development of diseases. The analytical expressions summarize the synergistic interactions among many molecules, which provides valuable insights into therapeutic interventions. In particular, a strategy for overcoming the limitations of mTOR inhibition is proposed for cancer therapy.
癌症与代谢性疾病之间的联系可能存在于一组共同生物分子之间的复杂相互作用网络中。通过应用奇异性和分岔分析，可以确定受 AKT 信号通路约束的表型，并将其映射到参数空间上，其中包括癌症和某些代谢性疾病。为了有效地感知生长因子和营养物质，AKT 通路必须具有一定的生理特性（敏感性、鲁棒性和适应性），考虑到这些特性，就可以确定正常反应区域。为了优化这些特性，AKT 蛋白的细胞内浓度必须足够高以使其酶饱和；正反馈的强度必须强于负反馈。该分析阐明了参数空间，并揭示了调节生物功能（细胞生长、存活、增殖和代谢）的系统级机制，以及它们的失调如何导致疾病的发展。分析表达式总结了许多分子之间的协同相互作用，为治疗干预提供了有价值的见解。特别是，提出了一种克服 mTOR 抑制局限性的策略，用于癌症治疗。
