Abstract 986: Reverse-engineered, forward-simulation of MEK-dependent molecular networks reveal novel regulators of cell cycle and cancer cell survival
Rina Gendelman, Heming Xing, Preeti Sarde, Olga K. Mirzoeva, Heidi S. Feiler, Joe W. Gray, Paul D. MCDONAGH, Iya G. Khalil, W. Michael · Cancer Research · 2012
Abstract ABSTRACT Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate non-intuitive behaviors. We applied a novel computational strategy to decipher causal relationships between signaling network components. Gene networks were constructed MEK from global gene expression profiles to model G1-S cell cycle arrest as a consequence of inhibition of MEK, a key component of the oncogenic RAF-MEK-ERK signal transduction pathway. Through forward-simulation of reverse-engineered networks candidate MEK-dependent regulators of the cell cycle were identified. The potential of the approach to infer causality is demonstrated by confirmed predictions of differential effects of two early-response transcription factors, IER2 and EGR1. Conventional linear regression analysis shows strong correlation of expression of both with MEK inhibition and cell cycle distribution, while only IER2 is predicted by our model and experimentally validated to have a causal effect on G1-S transition. Furthermore, we identify TRIB1 (tribbles homologue 1 drosophila) as a potent and novel cell cycle regulator. TRIB1 also mediates cross-talk to the NFkB pathway by enhancing p100 and IkBa-phosphorylation and degradation thus regulating cell survival and expression of cytokines crucial for tumor-stroma interaction. In agreement with this, knock-down of TRIB1 results in induction of apoptosis and sensitizes cells to cell killing induced by the death-receptor agonist TRAIL via upregulation of TRAIL receptor, DR5. Thus TRIB1 is a central regulator of cell cycle and survival and represents a potential therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 986. doi:1538-7445.AM2012-986