Exploring the Altered Dynamics of Mammalian Central Carbon Metabolic Pathway in Cancer Cells: A Classical Control Theoretic Approach

Abstract

BackgroundIn contrast with normal cells, most of the cancer cells depend on aerobic glycolysis for energy production in the form of adenosine triphosphate (ATP) bypassing mitochondrial oxidative phosphorylation. Moreover, compared to normal cells, cancer cells exhibit higher consumption of glucose with higher production of lactate. Again, higher rate of glycolysis provides the necessary glycolytic intermediary precursors for DNA, protein and lipid synthesis to maintain high active proliferation of the tumor cells. In this scenario, classical control theory based approach may be useful to explore the altered dynamics of the cancer cells. Since the dynamics of the cancer cells is different from that of the normal cells, understanding their dynamics may lead to development of novel therapeutic strategies.MethodWe have developed a model based on the state space equations of classical control theory along with an order reduction technique to mimic the actual dynamic behavior of mammalian central carbon metabolic (CCM) pathway in normal cells. Here, we have modified Michaelis Menten kinetic equation to incorporate feedback mechanism along with perturbations and cross talks associated with a metabolic pathway. Furthermore, we have perturbed the proposed model to reduce the mitochondrial oxidative phosphorylation. Thereafter, we have connected proportional-integral (PI) controller(s) with the model for tuning it to behave like the CCM pathway of a cancer cell. This methodology allows one to track the altered dynamics mediated by different enzymes.Results and DiscussionsThe proposed model successfully mimics all the probable dynamics of the CCM pathway in normal cells. Moreover, experimental results demonstrate that in cancer cells, a coordination among enzymes catalyzing pentose phosphate pathway and intermediate glycolytic enzymes along with switching of pyruvate kinase (M2 isoform) plays an important role to maintain their altered dynamics.

A control theoretic three timescale model for analyzing energy management in mammalian cancer cells

“…Here and represent the constants corresponding to and to take care of the relative strength of binding with gene [13] , [78] , [14] . We have considered binding constants to be in .…”

“…Thus, the initial reaction rate is increased by a multiplication factor. Then, we can write using modified Michaelis Menten kinetic equation [13] , [78] , [14] as where (could be one-to-many mapping) is the index for the reaction through which is produced. The terms and represent the kinetic rate constant and Michaelis Menten constant respectively.…”

“…Yet, it does not provide any supervisory controller that can regulate the enzyme/metabolite concentration to meet some particular requirements of a cell. Recently, we have developed a control theoretic approach to solve this problem [13] , [14] , [15] . Some investigations on crosstalk mechanism [16] and identifying properties [17] , [18] of signaling networks have also been developed.…”

Catestatin improves insulin sensitivity in diet-induced obese mice: in vivo and in silico validation

“…In order to formulate state transition equations, we integrated ER stress and insulin signaling pathway as depicted in Fig. S1 of Supplementary File S1 using the method in one of our previous investigations (37).…”

Computational properties of mitochondria in T cell activation and fate

“…The difference between current O 2 concentration and optimal (set) O 2 content defines the amount of Epo secretion [102]. On a molecular level, the PI controller model has been recently applied for mammalian central carbon metabolic pathway in normal and cancer cells [103]. At the organism level, the PI controller was proposed for homeostatic mechanisms responsible for inflammation and glucose level control [104].…”