Glutathione-Dependent Pathways in Cancer Cells.

ABSTRACT

The most abundant tripeptide-glutathione (GSH)-and the major GSH-related enzymes-glutathione peroxidases (GPxs) and glutathione S-transferases (GSTs)-are highly significant in the regulation of tumor cell viability, initiation of tumor development, its progression, and drug resistance. The high level of GSH synthesis in different cancer types depends not only on the increasing expression of the key enzymes of the γ-glutamyl cycle but also on the changes in transport velocity of its precursor amino acids. The ability of GPxs to reduce hydroperoxides is used for cellular viability, and each member of the GPx family has a different mechanism of action and site for maintaining redox balance. GSTs not only catalyze the conjugation of GSH to electrophilic substances and the reduction of organic hydroperoxides but also take part in the regulation of cellular signaling pathways. By catalyzing the S-glutathionylation of key target proteins, GSTs are involved in the regulation of major cellular processes, including metabolism (e.g., glycolysis and the PPP), signal transduction, transcription regulation, and the development of resistance to anticancer drugs. In this review, recent findings in GSH synthesis, the roles and functions of GPxs, and GST isoforms in cancer development are discussed, along with the search for GST and GPx inhibitors for cancer treatment.