Modulation of Tumor Cell Metabolism by the ATP Synthase Inhibitor Protein (IF1) and Role of the MiRNAs as Drivers of Drug Resistance

Metabolic reprogramming in cancer cells has recently been connected to IF1, a key regulator of ATP synthase activity, which is found to be overexpressed in many human carcinomas. Considering the pivotal role of mitochondria inside the cells, mitochondrial alteration is crucial for tumors to grow and IF1 may help tumor progression by conserving cellular ATP in hypoxic conditions. Although the inhibitor has being deeply investigated, its role in tumorigenesis and/or cancer progression is still debated. Therefore, we prepared stable IF1-silenced clones from the human osteosarcoma 143B cell line and assayed the main bioenergetic parameters, to examine both the role played by IF1 and the mechanism the inhibitor adopts in tumor cells to control mitochondrial mass, structure and function, besides regulate energy homeostasis. In our model, overall data indicate that the inhibitor protein can enhance the rate of ATP synthesis via OXPHOS, thus representing a successful strategy used by cancer cells to produce more energy and proliferate under oxygen availability. In addition, recent literature has clearly evidenced that epigenetic alterations play a crucial role in modifying genes expression and modulating cancer cell metabolism, sustaining tumor growth and dissemination. Moreover, these molecules have been recently addressed as responsible for chemoresistance in several common therapies, prompting further investigations over miRNAs-driven metabolic alterations. However, compelling data emerging from a microRNA expression profiling, revealed an up-regulation of four miRNAs in BRAF(V600E) mutation-carrying melanomas, when developing resistance to BRAF-I, the major breakthrough in the treatment of these poor-prognosis malignancies. Intriguingly, three of these miRNAs target SUFU, a protein inhibiting the Shh pathway, which is altered in various forms of cancer. Since therapeutic failure still accounts for death in over 90% of patients with metastatic cancers, we also focused on the role exerted by these miRNAs in the molecular mechanisms of drug-resistance.