Glutathione s-transferases in pediatric cancer

Abstract

The glutathione S-transferases (GSTs) are a family of ubiquitously expressed polymorphic enzymes important for detoxifying endogenous and exogenous compounds. In addition to their classic activity of detoxification by conjugation of compounds with glutathione, many other functions are now found to be associated with GSTs. The associations between GST polymorphisms/functions and human disease susceptibility or treatment outcome, mostly in adults, have been extensively studied and reviewed. This mini review focuses on studies related to GST epidemiology and functions related to pediatric cancer. Opportunities to exploit GST in pediatric cancer therapy are also discussed.

Keywords: drug resistance; epidemiology; glutathione S-transferase; microsatellite; pediatric cancer; therapeutic target.

Figure 1

A cartoon diagram of GSTP, a representative of a soluble GST enzyme. The N-terminal GSH-binding site (G-site, in yellow) and the C-terminal H-site (in purple) that binds the electrophilic substrate (in orange) are shown.

Figure 2

Cartoon model of how GSTP1–JNK and GSTP1–TRAF2 interactions modulate JNK and TNF-α signaling pathways. In non-stressed cells, GSTP1 form complexes with JNK and TRAF2 respectively. GSTP1–JNK interaction keeps JNK at low activity, while GSTP1–TRAF2 interaction competes against TRAF2–ASK1 binding which also leads to low JNK activity. In cells exposed to ROS or TNF-α, GSTP1 dissociates from the complexes and accumulates as oligomers, with resultant activation of JNK and downstream signaling pathways.

Figure 3

GST as targets in pediatric cancer treatment. GST non-specific inhibitors such as ETA or TER199 decrease the GST activity in tumors and sensitize tumor cells to chemotherapeutic agents. NBDHEX treatment of tumor cells interrupts GSTP1–JNK interaction which releases and activates JNK and results in tumor cell apoptosis. Prodrugs such as J-SK is activated specifically in tumors with high GST activity and selectively kills tumor cells.