Abstract 4913: Systematic analysis of LY30-induced sensitization of cancer cells to TRAIL
Yuan Shi, Lisa Tucker‐Kellogg, Jakob White, Shazib Pervaiz · Cancer Research · 2011
Abstract TRAIL (Tumor necrosis factor-Related Apoptosis Inducing Ligand) can selectively induce apoptosis in cancer cells expressing the TRAIL receptors. However, the problem of TRAIL resistance poses a significant therapeutic challenge. We recently demonstrated that the small molecule compound, LY30, sensitizes human cancer cells to TRAIL induced apoptosis via mechanisms that involve upregulation and/or oligomerization of the death receptors. However, the underlying biology of this phenomenon remains less well defined. Here we describe a mathematical modeling approach to tease out the molecular circuitry in the synergistic response of human cervical cancer cells (HeLa) to LY30 and TRAIL mediated apoptosis. We made use of ODE (Ordinary Differential Equation) to build two distinct pathway models for Hela cells to represent TRAIL-induced apoptosis (TRAIL Model) or LY30-induced cellular modification (LY30 Model) using the existing models and previous data sets. Moreover, in accordance with the experimental settings we integrated the LY30 Model and TRAIL Model as the CTM (Combination Treatment Model). The CTM showed that the level of simulated death correlated well with experimental observations, including the synergistic level of death from the combination treatment. However, simulation and experimental data exhibited numerous mismatches for some molecules in the pathway, such as differences in the slope and onset of the synergistic activation of caspase-8 and caspase-3. Such mismatch implies some flaw in the model and thus led us to additional measurement on the early dynamics of the species involved upstream of the apoptotic pathway. In specific, assessment of cFLIP, an inhibitor of caspase-8 activation, showed slight up-regulation very early after LY30 treatment (1 hour), followed by a significant down-regulation over prolonged exposure. By including such biological phenomenon into the CTM, we are able to improve the agreement between data and simulation while maintaining the consistency in synergistic cell death. Further model analysis revealed the fluctuation of FLIP is regulated by LY30 through a complicated ratio change between two main ROS (Reactive Oxygen Species), superoxide and hydrogen peroxide. These data provide a novel means for assessment of mechanisms for small molecule-induced sensitization of human cancer cells to TRAIL mediated apoptosis, with broader clinical implications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4913. doi:10.1158/1538-7445.AM2011-4913