# Non-Equilibrium Thermodynamic Approach to Ca\({}^{2+}\)-Fluxes in Cancer
## 4 Discussion and Conclusions  
Hyperpolarization determines the activation of the Ca\({}^{2+}\)-K\({}^{+}\) channel, which increases the Ca\({}^{2+}\) intracellular concentration [45]. Consequently, the Ca\({}^{2+}\)-K\({}^{+}\) channel results in a fundamental controller of the membrane electric potential. Proteins play a fundamental role in ion transport. Proteins in the cytosolic can be modified in their functions by phosphorylation or dephosphorylation. In this context, the H\({}^{+}\)-ATPase plays a fundamental role, because, it generates inflows of positive charges into the cell [73; 74; 75; 76]. Consequently, protein phosphorylation results in an important cellular regulatory mechanism, because many enzymes and receptors [77; 78] are activated or deactivated by phosphorylation, by involving kinase and phosphatase. Cancer and normal cells have different metabolic pathways; indeed, cancer cells must increase their metabolism in order to support their growth [79]. Consequently, we can consider that glycolysis is the cytoplasmic catabolism of glucose (C\({}_{6}\)H\({}_{12}\)O\({}_{6}\)) and it finishes with the inflow of pyruvate (CH\({}_{3}\)COCO\({}_{2}\)) into the Krebs cycle and the mitochondrion in the presence of oxygen, but, when oxygen supply is scarce, the pyruvate is converted into lactate (CH\({}_{3}\)CHOHCO\({}_{2}\)), and pumped out of the cell. As a consequence, the production of Hydrogen ions (H\({}^{+}\)) causes acidification, with the consequence of the stabilization of the Warburg metabolic cycle. In cancer cells, there is a net conversion of serine to glycine, catalysed by the cytosolic (SHMT1) or mitochondrial (SHMT2) serine hydroxymethyl transferase, and correlated with the cell proliferation rate and the DNA synthesis rate [79; 80]. Protein synthesis, proportional to the inflow rate of amino acids, requires energy: in cancer, around the 70% of glucose is converted to lactate during aerobic glycolysis [79; 81]. Therefore, our results point to the fundamental role played by ion transfer in any protein cycle. Indeed, ion channels transduce surface events to the cytosolic protein machineries. They couple the sensitivity of cooperative allosteric proteins to chemical and electrical signals: to do so, they use the energy released during the passive ions flows. Here, we have developed the study of the Ca\({}^{2+}\) flows and the related membrane potential variations, because changes in membrane potential can regulate Ca\({}^{2+}\) influx, which can impact T cell activation. This process is triggered by an elevation of the cytosolic free calcium concentration, which activates the Ca\({}^{2+}\)/PKC-dependent pathways that regulate progress from G0 into mitosis, with a related lymphocyte proliferation, as an effective immune response to cancer. The Ca\({}^{2+}\) inflow is obtained by means of hyperpolarization, which is induced through K\({}^{+}\) channel activation [5]. Here, a theoretical model to analyse the ion fluxes was developed using non-equilibrium thermodynamics. It represents a useful tool for future analysis, in order to develop a new approach to anticancer therapies, based on ion fluxes. Recently, the key role for Ca\({}^{2+}\) was shown to be in regulating cancer, in relation to oncogenes protecting against cell death, and perturbing intracellular Ca\({}^{2+}\) homeostasis. Indeed, oncoprotein B cell lymphoma 2 over-expression has been shown to be able to reduce steady-state Ca\({}^{2+}\) levels within the endoplasmic reticulum, reducing Ca\({}^{2+}\) transfer to the mitochondria, during apoptotic stimulation, and inhibiting apoptosis initiation [20; 21; 56]. Moreover, the protein mitogenic kinase Akt has been linked to Ca\({}^{2+}\) homeostasis control, pointing out its modulation function on the phosphorylation state of IP3R, by inhibiting its Ca\({}^{2+}\)-channel activity, and reducing the transfer of Ca\({}^{2+}\) from the endoplasmic reticulum to the mitochondria [25].