Modulation of Ferroptosis by microRNAs in Human Cancer.

Ferroptosis is a cell death pathway triggered by an imbalance between the production of oxidants and antioxidants, which plays an emerging role in tumorigenesis. It is mainly regulated at three different levels including iron metabolism, the antioxidant response, and lipid metabolism. Epigenetic dysregulation is a "hallmark" of human cancer, with nearly half of all human cancers harboring mutations in epigenetic regulators such as microRNA. While being the crucial player in controlling gene expression at the mRNA level, microRNAs have recently been shown to modulate cancer growth and development via the ferroptosis pathway. In this scenario, some miRNAs have a function in upregulating, while others play a role in inhibiting ferroptosis activity. The investigation of validated targets using the miRBase, miRTarBase, and miRecords platforms identified 13 genes that appeared enriched for iron metabolism, lipid peroxidation, and antioxidant defense; all are recognized contributors of tumoral suppression or progression phenotypes. This review summarizes and discuss the mechanism by which ferroptosis is initiated through an imbalance in the three pathways, the potential function of microRNAs in the control of this process, and a description of the treatments that have been shown to have an impact on the ferroptosis in cancer along with potential novel effects.

Targeting Mitochondrial Oncometabolites: A New Approach to Overcome Drug Resistance in Cancer.

Drug resistance is the main obstacle for a successful cancer therapy. There are many mechanisms by which cancers avoid drug-mediated death, including alterations in cellular metabolism and apoptotic programs. Mitochondria represent the cell's powerhouse and the connection between carbohydrate, lipid and proteins metabolism, as well as crucial controllers of apoptosis, playing an important role not only in tumor growth and progression, but also in drug response. Alterations in tricarboxylic acid cycle (TCA) caused by mutations in three TCA enzymes-isocitrate dehydrogenase, succinate dehydrogenase and fumarate hydratase-lead to the accumulation of 2-hydroxyglutarate, succinate and fumarate respectively, collectively known as oncometabolites. Oncometabolites have pleiotropic effects on cancer biology. For instance, they generate a pseudohypoxic phenotype and induce epigenetic changes, two factors that may promote cancer drug resistance leading to disease progression and poor therapy outcome. This review sums up the most recent findings about the role of TCA-derived oncometabolites in cancer aggressiveness and drug resistance, highlighting possible pharmacological strategies targeting oncometabolites production in order to improve the efficacy of cancer treatment.

Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance.

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.