Glutathione metabolism in cancer progression and treatment resistance

Abstract

Glutathione (GSH) is the most abundant antioxidant found in living organisms and has multiple functions, most of which maintain cellular redox homeostasis. GSH preserves sufficient levels of cysteine and detoxifies xenobiotics while also conferring therapeutic resistance to cancer cells. However, GSH metabolism plays both beneficial and pathogenic roles in a variety of malignancies. It is crucial to the removal and detoxification of carcinogens, and alterations in this pathway can have a profound effect on cell survival. Excess GSH promotes tumor progression, where elevated levels correlate with increased metastasis. In this review, we discuss recent studies that focus on deciphering the role of GSH in tumor initiation and progression as well as mechanisms underlying how GSH imparts treatment resistance to growing cancers. Targeting GSH synthesis/utilization therefore represents a potential means of rendering tumor cells more susceptible to different treatment options such as chemotherapy and radiotherapy.

Figure 1.

Maintenance of redox homeostasis in normal versus cancer cells. (A) Cells maintain a balance of antioxidants against ROS generated by the different physiological processes. (B) Cellular (Li et al., 2014a) redox states are maintained by modulating ROS production and elimination. Under normal conditions, cells maintain homeostasis by producing enough antioxidants to balance ROS production. However, because of hypoxia and metabolic alterations in cancer cells, increased amounts of ROS are generated, which are counteracted by enhanced antioxidant responses. However, when this balance is disrupted, high ROS levels can disrupt normal cellular machinery, triggering cell death.

Figure 2.

De novo biosynthesis of GSH. GSH is generated from glutamic acid, cysteine, and glycine in two successive ATP-dependent enzymatic steps. First, γ-glutamylcysteine is synthesized by a GCL, a reaction consuming glutamic acid and cysteine, and forming a γ-peptide bond. The second step is catalyzed by GSS, adding glycine to the C terminus of γ-glutamylcysteine, resulting in the final GSH product.

Figure 3.

Steps of GSH production and utilization. GGT is a membrane-bound enzyme that catalyzes the degradation of extracellular GSH, favoring the production of constituent amino acids for the synthesis of intracellular GSH. It also catalyzes the transfer of the glutamyl moiety of GSH, linked through the glutamate γ-carboxylic acid, to acceptor molecules including amino acids and peptides. Other steps of regulation include the expression levels of transporters of glutamate (ASCT2) and cystine (xCT).