Abstract A34: Novel chemical systems biology approach with the Berg Interrogative Biology® platform provides a window into hallmark shift in cancer metabolism

Abstract

Abstract Cancer is comprised of a subset of diseases that serve to dysregulate the molecular mechanisms that maintain cellular homeostasis. Otto Warburg described his seminal observation that cancer cells negotiated a switch towards anaerobic respiration from oxidative phosphorylation in return for sustained growth and evasion of normal cellular processes such as cell cycle control and apoptosis. The underlying mechanism that governs this phenomenon has yet to be firmly established. We employed a chemical systems biology approach to create a mechanistic window into this phenomenon. Cancer models that encompass in vitro cancer and normal cell models, perturbants, and conditions including hypoxia, hyperglycemia, and redox environments that parallel cancer pathophysiology were overlayed and interrogated with an ubidecarenone-based epimetabolic shifter. Total cellular proteome including response to perturbants and chemical interrogation were assessed using LC MS based methods. Cell-based assays utilizing a Seahorse XF24 analyzer were employed to understand glycolytic fluxes and oxidative metabolism. High-throughput protein and metabolite data were subjected to an artificial intelligence-based informatics analysis that generated data driven inference of cause and effect maps of proteins interactome including inference of molecular networks driving metabolic endpoints. Follow-up network biology analysis revealed molecular interactions of differential response to epimetabolic shifts induced by ubidecarenone in normal and tumor cell models. Novel causal pathways that recapitulate the Warburg phenomenon by an amalgamation of nuclear, mitochondrial, and extracellular matrix components were derived and further validated by wet lab experiments. Finally we took a pan-disease approach that spanned cancer, diabetes, and neurodegenerative disease models and generated insights into overarching molecular entities that drive aberrant metabolism in various disease pathologies. Citation Format: Niven R. Narain, Vivek K. Vishnudas, Viatscheslav R. Akmaev, Rangaprasad Sarangarajan. Novel chemical systems biology approach with the Berg Interrogative Biology® platform provides a window into hallmark shift in cancer metabolism [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A34.