Abstract
In humans, the glutathione S-transferases (GST) protein family is composed of seven members that present remarkable structural similarity and some degree of overlapping functionalities. GST proteins are crucial antioxidant enzymes that regulate stress-induced signaling pathways. Interestingly, overactive GST proteins are a frequent feature of many human cancers. Recent evidence has revealed that the biology of most GST proteins is complex and multifaceted and that these proteins actively participate in tumorigenic processes such as cell survival, cell proliferation, and drug resistance. Structural and pharmacological studies have identified various GST inhibitors, and these molecules have progressed to clinical trials for the treatment of cancer and other diseases. In this review, we discuss recent findings in GST protein biology and their roles in cancer development, their contribution in chemoresistance, and the development of GST inhibitors for cancer treatment.
Highlights
Glutathione S-transferases (GSTs) are a multigene family (EC 2.5.1.18) of eight dimeric enzymes that are classified based on their amino acid sequences and substrate specificity as alpha (A), kappa (K), mu (M), omega (O), pi (P), sigma (S), theta (T), and zeta (Z) [1].Depending on their subcellular location, glutathione S-transferases (GST) are grouped as cytoplasmic (A, P, M, S, T, Z), mitochondrial (K), or membrane-bound (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) [2]
Because GSTs are pivotal in drug metabolism, they were among the first cytosolic proteins to be structurally characterized
We have previously reported that GST Pi 1 (GSTP1) knockdown pancreatic ductal adenocarcinoma (PDAC)
Summary
Glutathione S-transferases (GSTs) are a multigene family (EC 2.5.1.18) of eight dimeric enzymes that are classified based on their amino acid sequences and substrate specificity as alpha (A), kappa (K), mu (M), omega (O), pi (P), sigma (S), theta (T), and zeta (Z) [1]. (1) the γ-glutamyl moiety is cleaved by γ-glutamyl transpeptidase; (2) the glycine is cleaved by dipeptidase; and (3) the cysteine is N-acetylated [5] In addition to their detoxification roles, GSTs are known for their functions in cell signaling, post-translational modification, and resistance to chemotherapeutic agents [6]. Similar to the detoxification process described above, antineoplastic drugs bound to GSH are expelled out of the cells by the membrane-bound GS-X pump, making cancer cells resistant to chemotherapy [10]. Since their discovery in 1961 in rat liver [11], GSTs have gained attention among cancer researchers. This review summarizes newly identified functions of GST proteins and their roles in the cellular signaling, metabolism, and survival of cancer cells
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