Microsomal glutathione transferase 1 in cancer and the regulation of ferroptosis

Abstract

Microsomal glutathione transferase 1 (MGST1) is a member of the MAPEG family (membrane associated proteins in eicosanoid and glutathione metabolism), defined according to enzymatic activities, sequence motifs, and structural properties. MGST1 is a homotrimer which can bind three molecules of glutathione (GSH), with one modified to a thiolate anion displaying one-third-of-sites-reactivity. MGST1 has both glutathione transferase and peroxidase activities. Each is based on stabilizing the GSH thiolate in the same active site. MGST1 is abundant in the liver and displays a broad subcellular distribution with high levels in endoplasmic reticulum and mitochondrial membranes, consistent with a physiological role in protection from reactive electrophilic intermediates and oxidative stress. In this review paper, we particularly focus on recent advances made in understanding MGST1 activation, induction, broad subcellular distribution, and the role of MGST1 in apoptosis, ferroptosis, cancer progression, and therapeutic responses.

Keywords: Apoptosis; Biomarker; Cancer; Drug resistance; Ferroptosis; Metastatic potential; Microsomal glutathione transferase; Polymorphisms; Prognosis; Survival.

Fig. 1

Microsomal glutathione transferase 1 (MGST1) plays a key role in inhibiting ferroptosis in cancer cells. Ferroptosis occurs by three steps: reduced activity of the cysteine-glutamate antiporter (system Xc−); inhibition of selenocysteine-containing glutathione peroxidase 4 (GPX4); iron-dependent generation of lipid peroxides through Fenton chemistry and the enzymes arachidonate lipoxygenase (ALOX) and NADPH oxidases. Polyunsaturated-fatty-acid-containing phospholipids (PL-PUFA) in membrane undergo lipid peroxidation, which directly destroys the cellular membrane, thereby causing cell death via ferroptosis. MGST1 or GPX4 reduces lipid peroxides to lipid alcohols by oxidizing glutathione (GSH), thereby protecting cells from ferroptosis. In addition, MGST1 can reduce the generation of lipid peroxides (·OH) by binding to arachidonate 5-lipoxygenase (ALOX5) and promoting the melanin biosynthesis. Binding of melanin with ferrous ions (Fe²⁺) decreases the yield of hydroxyl radical through Fenton chemistry. Ferroptosis plays a pivotal role in tumor suppression and inducing ferroptosis has been demonstrated to reverse resistance of cancer to common drug-, targeted- and immunotherapies. Inhibition of MGST1 and induction of ferroptosis may be a novel strategy for cancer therapy.