Sodium-calcium exchangers and cancer: role in calcium homeostasis, energy metabolism and tumor proliferation

Abstract

Cancer is one of the main causes of death in the world and it has become an important public health problem, due to its increased incidence in the population, toxicity and side effects of treatment, resistance to available therapeutic options, causing a significant impact on economic to health systems. Tumor cells exhibit molecular alterations ('the hallmarks of cancer') that provide them adaptive and proliferative advantages, including independence from growth signals, genetic instability, evasion of apoptosis and immune system, metastatic capacity, and metabolic reprogramming. However, the mechanisms involved in such alterations are not fully understood and may vary with the type and stage of the tumor. For this reason, studies on tumor biology field, mainly aimed at understanding molecular alterations, are essential for controlling the disease. Calcium is an important intracellular second messenger, capable of regulating from cell signaling to energy metabolism regulation under physiological conditions. However, alterations in calcium homeostasis and its signaling and transporters network have been described in tumors. Although many calcium channels and transporters have been extensively investigated in cancer, studies on the role of the sodium-calcium exchanger (NCX) are scarce. Our research group showed that NCX acts in the reverse mode in melanoma, promoting sodium efflux and calcium influx. In addition, Prof. Amoroso's group (Università Politecnica delle Marche, Ancona, Italy) was pioneer in showing the functional interaction between NCX and the excitatory amino acid transporter (EAAT) and its impacts on cellular energy metabolism in the central nervous system. Thus, considering the metabolic reprogramming exhibited by tumor cells, including the dependence on glutamine/glutamate as a source of energy, to investigate the functional interaction NCX/EAAT, changes in calcium homeostasis, and reprogramming of tumor metabolism is of fundamental importance to the field. Therefore, this project aims to evaluate the expression of the Na+/Ca2+ exchanger (NCX) and the mitochondrial Na+/Ca2+/Li+ exchanger (NCLX) in tumor cells, to correlate such expression with amino acid transporters, and to characterize functionally its role in the alterations of Ca2+ homeostasis and tumor energy metabolism. To that end, transcriptome data from cancer patients will be analyzed to assess the expression of NCX and its correlation of glutamine and glutamate transporters. In addition, using human melanoma and glioblastoma tumor cell lines in vitro, the expression and functional characterization of NCX/NCLX and its interaction with EAAT will be evaluated. Furthermore, the effects of its inhibition and the availability of substrates on tumor energy metabolism will be addressed. The results obtained in this project will bring advances to the understanding of molecular aspects related to tumor biology, more specifically about the impacts of NCX/NCLX on tumor metabolism. (AU)