Abstract
Metastatic cancer is a complex positive feedback loop system. Such as system has a tendency to acquire extreme robustness. Signaling pathways controlling that robustness can fail completely if an essential element from the signaling is removed. That element is a locus of fragility. Targeting that locus represents the best way to target the cancer robustness. This prospect presents another locus of fragility in signaling complex system network, controlling the cell cycle progression through the PI3K/AKT/mTOR/RAN pathway and cell migration and angiogenesis through the VEGF/PI3K/AKT/NO/ICAMβ1 pathway. The locus of fragility of these pathways is AKT, which is regulated by a balance of catalase/H~2~O~2~ or by AKT inhibitor. Tiny and trivial perturbations such as change in redox state in the cells by antioxidant enzyme catalase, scavenging H~2~O~2~ signaling molecule, regulates robust signaling molecule AKT, abolishing its phosporilation and inducing cascading failure of robust signaling pathways for cell growth, proliferation, migration, and angiogenesis. An anticancer effect of the antioxidant is achieved through the AKT locus, by abolishing signals from growth factors VEGF, HGF, HIFβ1Ξ± and H~2~O~2~. Previously reported locus of fragility nitric oxide (NO) and locus AKT are close in the complex signaling interactome network, but they regulate distinct signaling modules. Simultaneously targeted loci represents new principles in cancer robustness chemotherapy by blocking cell proliferation, migration, angiogenesis and inducing rather slow then fast apoptosis leading to slow eradication of cancer. J. Cell. Biochem. 104: 2071β2077, 2008. Β© 2008 WileyβLiss, Inc.