Glutathione S-Transferases in Cancer

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.

Keywords: GST inhibitors; Glutathione S-transferases (GSTs); JNK; antioxidants; apoptosis; cancer-cell signaling; chemoresistance; glutathionylation; metabolism; oxidative stress; patient survival; xenobiotic compounds.

Figure 1

Structure of Glutathione S-transferase Pi 1 (GSTP1) (Protein Data Bank ID: 6GSS). (A) Homodimer assembly of GSTP1 showing G- and H-sites. (B) Magnified view of the G-site that is occupied by the ligand glutathione (GSH) (shown in light green). (C) Glutathione (light green) forms hydrogen-binding interactions with the surrounding amino acids found in the G-site pocket of GSTP1.

Figure 2

Multifarious roles of GSTP1 in cell signaling. (A) Under oxidative stress, the interaction between GSTP1 and c-Jun N-terminal kinase 1 (JNK1) is deterred and leads to phosphorylation of c-Jun and transcription of target genes. Similarly, in the absence of GSTP1, tumor necrosis factor (TNF)-receptor-associated factor 2 (TRAF2), and apoptosis signal-regulating kinase (ASK1) interact and cause phosphorylation of c-Jun. (B) Phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK) in GSTP1 knockdown cells inhibits the mechanistic target of rapamycin (mTOR) pathway and impairs protein synthesis.

Figure 3

Structure of inhibitors that bind to the G-site of GST proteins. (A) Covalent inhibitor benzene sulfonyl fluoride (BSF)-type ligand (X=Cl, F) and (B) 1-chloro-2,4-dinitrobenzene (CDNB).

Figure 4

Structure of covalent inhibitors that specifically bind to the active site of Glutathione S-transferase Omega-1 (GSTO1) protein. (A) ML175 and (B) KT53.

Figure 5

Structure of inhibitors that bind to the G-site of GST proteins. (A) 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), (B) ethacrynic acid, (C) LAS17, and (D) MC3181 (2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol), an NBDHEX analogue.

Figure 6

Structure of GSH peptidomimetics (A) TLK117 and (B) Ezatiostat (TLK199).

Figure 7

Structure of natural compounds that bind to the GST proteins and inhibit their activity. (A) Piperlongumine is a bioactive alkaloid obtained from Piper longum, (B) Curcumin is an antioxidant obtained from Curcuma longa, and (C) Carnosic acid is an antioxidant and an anti-inflammatory agent obtained from Rosmarinus officinalis.

Figure 8

Expression of GST proteins is negatively correlated with patient survival for some human cancers. The Human Protein Atlas was mined for Glutathione S-transferase Alpha 1 (GSTA1) (A–C), Glutathione S-transferase Kappa 1 (GSTK1) (D–F), Glutathione S-transferase Mu 1 (GSTM1) (G–I), and Glutathione S-transferase Pi 1 (GSTP1) (J–L) mRNA expression in cancer patients relative to their corresponding years of survival post-diagnosis. The patients were divided in high- (red) and low- (blue) GST expressing groups. The Kaplan–Meier survival plots were constructed in RStudio.