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Lv, N.; Huang, C.; Huang, H.; Dong, Z.; Chen, X.; Lu, C.; Zhang, Y. Overexpression of Glutathione S-Transferases in Human Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/52041 (accessed on 01 July 2024).
Lv N, Huang C, Huang H, Dong Z, Chen X, Lu C, et al. Overexpression of Glutathione S-Transferases in Human Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/52041. Accessed July 01, 2024.
Lv, Ning, Chunyan Huang, Haoyan Huang, Zhiqiang Dong, Xijing Chen, Chengcan Lu, Yongjie Zhang. "Overexpression of Glutathione S-Transferases in Human Diseases" Encyclopedia, https://encyclopedia.pub/entry/52041 (accessed July 01, 2024).
Lv, N., Huang, C., Huang, H., Dong, Z., Chen, X., Lu, C., & Zhang, Y. (2023, November 24). Overexpression of Glutathione S-Transferases in Human Diseases. In Encyclopedia. https://encyclopedia.pub/entry/52041
Lv, Ning, et al. "Overexpression of Glutathione S-Transferases in Human Diseases." Encyclopedia. Web. 24 November, 2023.
Overexpression of Glutathione S-Transferases in Human Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/antiox12111970

Glutathione S-transferases (GSTs) are a major class of phase II metabolic enzymes. Besides their essential role in detoxification, GSTs also exert diverse biological activities in the occurrence and development of various diseases. Much research interest has been paid to exploring the mechanisms of GST overexpression in tumor drug resistance. Correspondingly, many GST inhibitors have been developed and applied, solely or in combination with chemotherapeutic drugs, for the treatment of multi-drug resistant tumors. Moreover, novel roles of GSTs in other diseases, such as pulmonary fibrosis and neurodegenerative diseases, have been recognized, although the exact regulatory mechanisms remain to be elucidated.

glutathione S-transferases overexpression chemoresistance neurodegenerative disease pulmonary fibrosis GST inhibitors

1. Introduction

Glutathione S-transferases (GSTs) were first isolated from cytoplasm in rat liver tissue in the 1960s and have been of continuous research interest ever since [1]. Mammalian GSTs are a large family that can be further divided into three classes, namely cytosolic GSTs, mitochondrial GSTs, and microsomal GSTs, according to their cellular localizations [2]. Among them, cytosolic GSTs are probably the most well-studied GSTs and are widely expressed in various types of cells [3].
Cytosolic GSTs exist as homodimers or heterodimers in the cytoplasm of cells, with a subunit length between 200 and 250 amino acids and a molecular weight between 23 and 28 kDa [4][5][6]. Cytosolic GSTs are classified into seven classes based on the similarity of amino acid sequences and structural features: Alpha (α), Sigma (σ), Mu (μ), Pi (π), Omega (ω), Theta (θ), and Zeta (ζ) [7][8][9]. In mammals, the sequence identity of cytosolic GST isozymes in the same class is >40%, and the sequence identity of isozymes between classes is <25% [10]. Each isoform is encoded by a unique gene, and the coding genes are in different chromosomal locations. Cytosolic GSTs are extensively expressed in human tissues. Cytosolic GSTs have a variety of biological functions: (1) catalysis of conjugation reactions of reduced glutathione (GSH) to electrophilic substances (including drugs), electrophilic drug metabolites, and endogenous electrophiles [5]; (2) catalysis of reduction in organic hydroperoxides; (3) regulation of various cellular signaling pathways, such as the mitogen-activated protein (MAP) kinase pathway via the inhibition of c-Jun N-terminal kinase 1 (JNK1) and apoptosis signal-regulating kinase 1 (ASK1) [11]; (4) post-translational modification of various proteins by S-glutathionylation or de-glutathiolation [12]; and (5) contribution to multidrug resistance to chemotherapeutic drugs and protection of cancer cells against apoptosis [13].

2. GSTs and Tumor Multidrug Resistance

Chemotherapy is one of the most common and effective treatments for cancers. However, tumor cells are known to often develop multidrug resistance (MDR) during chemotherapy, which is the main reason for therapeutic failure [7]. The American Cancer Society estimates that more than 90% of cancer deaths are associated with MDR. MDR is defined as loss of sensitivity to antineoplastic drugs with distinct structures and different molecular targets. Many mechanisms have been proposed to explain MDR, such as the decrease in intracellular drug concentrations due to efflux pump induction, the mutation of drug targets, the upregulated metabolic detoxification, and the enhanced DNA damage repair function [14]. The mechanism of drug resistance may involve a variety of proteins. One type of MDR is based on overexpression of efflux pumps at the plasma membrane, such as P-gp, MRP1, and BCRP, resulting in strongly reduced intracellular drug concentrations [12]. Overexpression of P-gp is considered to play an important role in MDR and is the main reason for the failure of chemotherapy [15]. The other type of MDR is based on overexpression of GSTs, which can result in direct detoxification of chemotherapeutics and/or inhibition of the MAPK signaling pathway [12]. GSTs can cooperate with efflux transporters and multidrug resistance proteins to protect tumor cells from the cytotoxicity of anticancer drugs [16].
The role of GSTs, especially GSTP1, in the development of cancer has attracted attention in recent years. A study showed that the expression of GST isozymes is upregulated in 60 human tumor cell lines, both at mRNA and protein levels. GSTP1 was shown to be the most abundant isozyme in all of these cell lines [17][18]. Overexpression of GSTP1 has been reported to involve cancer cell resistance to chemotherapeutics, such as resistance of ovarian cancer cells against carboplatin and cisplatin, adriamycin-resistance of breast cancer cells and prostate cancer cells, resistance of gastric cancer cells against fluorouracil (5-FU) and cisplatin, and resistance of neurogliomas against cisplatin and irinotecan [19][20][21][22][23]. The roles of other GST isoforms, including GSTA, GSTM, GSTO, and GSTT, in MDR have also been investigated. For instance, it is demonstrated that GSTA played an essential role in the detoxification of chlorambucil via catalyzing the GSH conjugation reaction of this alkylating reagent [24]. Table 1 lists the involvement of different GST isoforms in drug-resistant chemotherapies and related antineoplastic drugs. Several GST isoforms have been shown to play essential roles in tumorigenesis and metastasis. For example, in breast cancer cells, chemotherapy-induced GSTO1 expression leads to chemotherapy resistance and promotes metastasis. The GSTO1 inhibitor S2E increased the rate of apoptosis by tamoxifen in MDA-MB-231 cells [25]. Wang et al. [26] showed that overexpressed GSTA1 not only promotes the proliferation of lung cancer cells but also stimulates metastasis of lung cancer cells by promoting epithelial–mesenchymal transition (EMT).
Table 1. Involvement of GSTs in multidrug resistance in cancer chemotherapeutics.
Isozyme Types Types of Cancer Anti-Tumor Drugs References
GSTP1 Breast cancer, ovarian cancer, colorectal cancer, lung cancer, gastric cancer, glioma, human squamous cell carcinoma, glioblastoma multiforme (GBM), bladder cancer, osteosarcoma, mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), prostate cancer, esophageal cancer Cisplatin, carboplatin, doxorubicin, cyclophosphamide, paclitaxel, docetaxel, melphalan, etoposide, oxaliplatin, fluorouracil, irinotecan, cytarabine, gemcitabine, bortezomib [17][23][27][28][29][30]
GSTA1 Colorectal cancer, leukemia, lung cancer Bacitracin, melphalan, chlorambucil, thiotepa, cyclophosphamide, imatinib, cisplatin [17][24][26][31][32]
GSTM1 Intracranial tumors (ICT), liver cancer, melanoma Thiotepa, oxaliplatin, vincristine [16][17][27][33][34]
GSTM3 Breast cancer, glioblastoma multiforme (GBM) BCNU, temozolomide (TMZ) [17][23][25][35]
GSTO1 Breast cancer, pancreatic cancer, ovarian cancer Cisplatin [23][36]
GSTT1 Ovarian cancer, glioblastoma multiforme Paclitaxel, carboplatin, BCNU [17][37][38]

2.1. Nuclear Localization of GSTP1

In addition to the high expression of GSTP1 in tumor tissues, the subcellular localization in tumor cells has been associated with oncogenic effects [2]. In normal cells, GSTP1 is mainly expressed in the cytoplasm, whereas it is found that in oral squamous cell carcinoma, GSTP1 is mainly located in the nucleus [39]. Nuclear GSTP1-negative cells have previously been shown to be more sensitive to cytotoxic drugs than nuclear GSTP1-positive cells, suggesting that the nuclear localization of GSTP1 is associated with drug resistance [40]. GSTP1 has been reported to be expressed in the nuclei of glioma cells and uterine cancer cells, and its nuclear localization showed a negative correlation with patient survival [41][42]. Rolland et al. [30] elaborated on the effect of GSTP1 nuclear translocation inhibitors on the chemotherapy sensitivity in mantle cell lymphoma (MCL) cells. It was shown that inhibition of GSTP1 nuclear translocation with agaricus bisporus lectin (ABL) was able to increase the sensitivity of MCL to doxorubicin (DOX), cisplatin (CDDP), cytarabine (Ara-C), gemcitabine (GEM), and bortezomib [30]. It is proposed that the nuclear localization of GSTP1 is chemotherapy-induced and contributes to the drug resistance of cancer cells.

2.2. Effects of GSTs on Glycolysis

Glycolysis is one of the most important processes in cellular energy metabolism, converting glucose in cells to provide the energy needed for life activities. In tumor tissues, aerobic glycolysis with abnormal release of adenosine triphosphate (ATP) and lactate, which is known as the Warburg effect, fulfills the requirement of rapid tumor growth [35][43][44]. Lactate dehydrogenase A (LDHA) is known to be relevant to angiogenesis, proliferation, immune evasion, and metastasis during tumorigenesis [45]. Furthermore, altered glycolytic metabolism in tumor cells is highly correlated with the prognosis of tumor patients and therefore can be used as a target for cancer therapy [46]. A previous study showed that GSTM3 was highly expressed in TMZ-resistant T98G cells and affects glycolysis [35]. The activity of LDHA and the glycolytic end product L-lactate level were significantly reduced in T98G cells along with GSTM3 gene suppression, which implied that GSTM3 downregulation might prevent cell invasion. Interestingly, Wang et al. [47] found that GSTM3-silenced pancreatic cancer (PC) cells exhibited increased levels of glycolysis, whereas the overexpression of GSTM3 showed a decrease in glycolysis. This suggested that GSTM3 may provide a potential therapeutic strategy for PC treatment.

2.3. Effects of GSTs on DNA Repair

DNA repair is a cellular response to DNA damage that will restore the DNA structure to its original form. However, it sometimes does not completely eliminate the DNA damage but only enables the cell to tolerate the DNA damage and continue to survive. Cancer cells use residual DNA repair capacity to repair the damage caused by DNA replication stress and genotoxic antitumor drugs [48]. DNA topoisomerases are crucial nuclear enzymes in DNA replication and repair. Many chemotherapeutic drugs target DNA topoisomerases and interfere with DNA replication to exert their anti-tumor activity [49]. It has been shown that GSTT1 expression is significantly upregulated in chemotherapy-resistant serous ovarian cancer (SOC) cells and that inhibition of GSTT1 expression negatively influenced the proliferation of SOC cells, thereby enhancing their sensitivity to paclitaxel/carboplatin [37]. Immunoprecipitation results showed a significant interaction between GSTT1 and Topo I in vitro, and these two enzymes expressed synergistically in drug-resistant cancer cells, suggesting that the mechanism of GSTT1-mediated drug resistance may be involved in DNA repair during chemotherapy of SOC cells [37]. To date, the mechanism of this interaction remains to be clarified.

2.4. Effects of GSTs on Autophagy

Autophagy is a tightly regulated intracellular degradation process. As a dynamic circulator system, autophagy provides energy and components for cell renewal and maintenance of homeostasis [50]. The consequences of autophagy can be contradictory based on the stage of tumorigenesis. In non-tumor cells and at the early stage of tumor development, autophagy functions as a tumor suppressor, while in already-established tumors, autophagy promotes cancer cell survival [51]. However, the roles of autophagy in cancers vary with different types of tumors. In pancreatic cancer cells, the inhibition of autophagy leads to cell growth inhibition [52]. Fu et al. [33] showed that the chemoresistance to oxaliplatin in hepatocellular carcinoma cells might be mediated by GSTM1-regulated autophagy. In that study, GSTM1 silencing resulted in a significant decrease in the number of oxaliplatin-induced autophagic vesicles. Nevertheless, other studies have shown that activation of autophagy presented beneficial effects that facilitated lapatinib to overcome drug resistance and increase its toxicity in tumor cells [53]. Therefore, the different roles of autophagy and an in-depth understanding of the genetic backgrounds of specific tumor types are particularly important for the understanding of the involvement of GSTs in the autophagy process, which determines the fate of cancer cells.

2.5. Effects of GSTs on Ferroptosis

Ferroptosis is a recently identified form of programmed cell death that is distinct from necrosis, apoptosis, and autophagy and was first described in 2012 [54]. It is considered to be an iron-dependent form of cell death and characterized by the involvement of lipid peroxidation, which ultimately leads to the rupture of the cytoplasmic membrane and the release of cellular contents. The role of ferroptosis in cancer treatment is gaining attention since it is recognized that induction of ferroptosis may be beneficial for more efficient elimination of cancer cells [55]. However, so far, ferroptosis-based therapy has been found to be effective in only a small number of cancer types, whereas most cancers encounter problems of ferroptosis resistance [56][57][58]. Wang et al. [59] first found that GSTZ1 could enhance sorafenib-induced ferroptosis by inhibiting the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (NRF2/GPX4) signaling pathway in hepatocellular carcinoma (HCC) cells. In this study, GSTZ1 was found to be downregulated in sorafenib-resistant HCC cells, while recovery of GSTZ1 enhanced sorafenib-induced ferroptosis in HCC cells. This suggests that GSTZ1 acts as a negative regulator of sorafenib resistance via the ferroptosis pathway. In contrast, microsomal glutathione S-transferase 1 (MGST1) was shown to negatively regulate and also promote resistance to ferroptosis in pancreatic ductal adenocarcinoma (PDAC) cells [60].

3. GSTs and Parkinson’s Disease

Parkinson’s disease is a movement disorder caused by degenerative changes in dopaminergic neurons in the substantia nigra of the skull, resulting in a decrease and deficiency of striatal dopamine. Oxidative stress has been reported to play a key role in the pathogenesis of PD [61]. Because of its relatively weak antioxidant capacity, the central nervous system is highly sensitive to oxidative stress, with the substantia nigra region being the most sensitive and vulnerable site [62]. A comparison of protein profiles using a quantitative proteomics technique revealed that GSTP1 is overexpressed in cortical neuronal cells in the late stages of PD [63]. In that study, GSTP1 overexpression was found to attenuate oxidative stress and ER stress as well as prevent rotenone-induced neurotoxicity. This suggests that GSTP1 may be able to delay disease progression in PD. Some studies suggested that the neuroprotective effects of GSTP1 may be related to its inhibition of JNK activation and prevention of the subsequent cell death cascade [64]. In addition, the overexpression of GSTS1 was shown to inhibit neurodegeneration [65]. Notably, GSTO1 may mediate the inflammatory response in the pathogenesis of PD and Alzheimer’s disease (AD) by participating in the regulation of interleukin-1β activity, and this inflammatory response is thought to be a contributing mechanism in the pathogenesis of PD and AD [66][67]. GSTM2 has been shown to be expressed in the substantia nigra of the human brain and exhibits a neuroprotective role by efficiently catalyzing the GSH-conjugation of ortho-quinone metabolite of dopamine, thereby protecting against its toxicity, redox cycling, and apoptosis, processes that have been associated with PD and schizophrenia [68]. The enzymatic activities of the GSTA, P, and T classes are substantially low or even negligible compared to GSTM2, while GSTM1 was slightly less effective than GSTM2.

4. GSTs and Epilepsy

Epilepsy is a chronic disease in which sudden abnormal discharges of neurons in the brain lead to transient brain dysfunction and muscular contractions. The pathogenesis of epilepsy is complex, and clinical data and experimental studies suggest that free radicals generated by oxidative reactions in mitochondria during disease onset may be the most critical cause of epilepsy pathogenesis. An association study showed that deficiency of GSTT1 is a risk factor for epilepsy, while genotypes of GSTM1 and GSTP1 showed no effect [69]. However, a very high GSTP1 expression was found in the neuroglia of epileptic foci in brain specimens from patients with refractory epilepsy when compared to patients with non-refractory epilepsy [70]. These GSTP1-positive astrocytes were widely present in the seizure lesions.

5. GSTs and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic, and interstitial lung disease of unknown etiology, with the pathogenesis not fully elucidated. It has been shown that intracellular GST levels are increased in pulmonary fibrosis cells from IPF mice models and patients, suggesting that GSTs may play an important role in promoting pulmonary fibrosis formation [71]. The combination treatment with the GSTP inhibitor TLK117 and pirfenidone was found to be more effective than pirfenidone alone in a mouse model of pulmonary fibrosis. Pulmonary epithelial cell apoptosis promotes fibroblast activation and remodeling and may play a key role in the pathogenesis of IPF. McMillan et al. [72] demonstrated that S-glutathionylation of FAS by GSTP stimulates apoptosis of pulmonary epithelial cells, which may result in pulmonary fibrosis. These results showed that FAS-GSTP interaction was increased in lung epithelial cells of IPF patients and that the use of GSTP inhibitor TLK117 attenuated the level of S-glutathionylation and fibroblast remodeling [72]. This suggests that inhibition of GSTP in the airway may be a new strategy for the treatment of pulmonary fibrosis.

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Subjects: Pharmacology & Pharmacy
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ning Lv
,
Chunyan Huang
,
Haoyan Huang
,
Zhiqiang Dong
,
Xijing Chen
,
Chengcan Lu
,
Yongjie Zhang
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Revisions: 2 times (View History)
Update Date: 27 Nov 2023
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