Glutathione S-transferase polymorphisms: cancer incidence and therapy

Abstract

The super family of glutathione S-transferases (GSTs) is composed of multiple isozymes with significant evidence of functional polymorphic variation. Over the last three decades, data from cancer studies have linked aberrant expression of GST isozymes with the development and expression of resistance to a variety of chemicals, including cancer drugs. This review addresses how differences in the human GST isozyme expression patterns influence cancer susceptibility, prognosis and treatment. In addition to the well-characterized catalytic activity, recent evidence has shown that certain GST isozymes can regulate mitogen-activated protein kinases or can facilitate the addition of glutathione to cysteine residues in target proteins (S-glutathionylation). These multiple functionalities have contributed to the recent efforts to target GSTs with novel small molecule therapeutics. Presently, at least two drugs are in late-stage clinical testing. The evolving functions of GST and their divergent expression patterns in individuals make them an attractive target for drug discovery.

Figures

Figure 1

Under non-stressed conditions, GSTπ inhibits JNK phosphorylation by sequestering JNK/c-Jun. Exposure to anticancer drugs or oxidative stress can alter the redox potential of the cell resulting in the oligomerization of GSTπ and the dissociation of the GSTπ:JNK complex. JNK can then become phosphorylated and subsequently activate downstream kinases and transcription factors. In some cases, transient or low exposure to stress can induce cell proliferation. During prolonged or high exposure, apoptosis can be induced.

Figure 2

GSTμ and thioredoxin (Trx) can act as inhibitors of ASK1. Stresses such as heat shock or reactive oxygen species can result in the release of ASK1 from the GSTμ:ASK1 or TRX:ASK1 complex (respectively). ASK1 oligomerizes and is activated through autophosphorylation, which in turn activates downstream kinases such as MKK4/MKK7, MKK3/MKK6, JNK and p38. The fate of the cell (either proliferation or apoptosis) is dependent upon the time/concentration exposure to the stress.

Figure 3

Nitric oxide (NO) can react with GSH to form GSNO and subsequently a glutathionyl radical GS· and nitroxyl (HNO). This can react with GSH to give N-hydroxysulfenamide (GS-NHOH), which can rearrange to generate a sulfinamide (GS(O)NH2). Reaction of GS(O)NH2 with GSH forms GSH disulfide-S-oxide (GS(O)SG) or can be further oxidized to sulfinic acid (GS(O)OH) and NH3. The key intermediates leading to the synthesis of GS(O)SG are the sulfinamides (GS(O)NH2 and GS(O)-NH-SG). The reaction of GS(O)SG or GS· with a reduced protein thiol (R-SH) leads to the formation of a mixed disulfide.