GPCRs, at the Crossroad of Distortions in Extracellular Microenvironment and Intracellular Energetics Homeostasis, a New Model for 21st Century Cancer Therapeutics

Abstract

G-protein coupled receptors (GPCRs) have evolved in complexity and are most widely used by metazoan for essential physiological functions. They are involved in mechanisms that allow cells to receive signals from their environment and react to them. Nearly 20% of human tumors harbor mutations in GPCRs and aberrant expression and activity of G proteins and G-protein-coupled receptors are frequently associated with tumorigenesis. In this article, we review and discuss the roles of GPCRs in normal and neoplastic transformation. This could be looked upon the crossroad of distortions in extracellular microenvironment and intracellular energetics landscape homeostasis. We hypothesize that GPCRs have taken over the role of sensing cellular energetics status and are involved in regulation of signal transduction and gene expression. We also present evolutionary biology perspectives lending further support to the above mentioned notions. We propose that however complex and intricate these pathways and interactions seem, they are all guided by one elegant and simple law, namely keeping the network entropy of the cell at the minimum possible level which correlates inversely with its free energy. Cancer cells are in abnormal state(s) characterized by dysregulated energetics. Based on this view of malignant transformation, further studies and measurements of cellular energetics landscape in both normal cell and its malignant counterpart and mathematical modeling could open the way for future cancer therapeutics strategies. We propose that our future cancer treatment strategies should target conversion rather than destruction of the malignant cell which is the current dominant theme of cancer therapy that has faced insurmountable barriers as evidenced by the short and limited survivorship of patients diagnosed with advanced malignant disorders. Keywords: G-protein coupled receptors, evolution, cancer, multicellular unit, environment, network entropy, free energy