Glutathione S‐transferase Pi 1 is a valuable predictor for cancer drug resistance in esophageal squamous cell carcinoma

Ogino, Shiro; Konishi, Hirotaka; Ichikawa, Daisuke; Matsubara, Daiki; Shoda, Katsutoshi; Arita, Tomohiro; Kosuga, Toshiyuki; Komatsu, Shuhei; Shiozaki, Atsushi; Okamoto, Kazuma; Kishimoto, Mitsuo; Otsuji, Eigo

doi:10.1111/cas.13896

Cited by 16 publications

(10 citation statements)

References 33 publications

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“…In addition, the effect of GSTP1 on cell proliferation and apoptosis has been examined in esophageal squamous cell carcinoma cell lines. Knocking down GSTP1 in cancer cells significantly decreases cell proliferation, while early apoptosis occurs [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Lei

Alvarado³

et al. 2020

J Hematol Oncol

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Background Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. Methods High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. Results We identified a small molecular inhibitor, “MNPC,” that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Conclusions Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.

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Section: Discussionmentioning

confidence: 99%

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Lei

Alvarado³

et al. 2020

J Hematol Oncol

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“…It should be noted that several of the identified proteins have already been reported as binding partners, e.g., vimentin; protein disulfide-isomerases PDIA1, PDIA3, and PDIA6; COP9 signalosome complex subunit 4; and elongation factor 1 alpha-1 [ 16 , 17 , 19 , 40 ]. However, only in rare cases have efforts been made to characterize their relevance for cell sensitivity [ 41 , 42 , 43 , 44 , 45 ]. To produce detailed studies, we selected one protein only identified in ovarian cancer cells, one found only in colorectal cancer cells, and one identified in all four cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…GSTP1 is believed to play a significant role in the inactivation of drugs by conjugating them to glutathione with subsequent transportation out of the cells via, e.g., membrane-bound MRP efflux pumps [ 48 , 58 , 59 ]. The enzyme has been found to be overexpressed in a variety of solid tumors and has also been linked to malignant potential and poor outcomes [ 45 , 60 ]. Under normal conditions, GSTP1 is bound to c-Jun N -terminal kinase (JNK), preventing its phosphorylation and therefore inhibiting downstream signaling [ 30 , 33 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity

Möltgen

Piumatti

Massafra

et al. 2020

Cells

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Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.

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“…In a recent study, there was a significant association between GSTP1 expression in resected tissue and biopsy samples in patients with esophageal squamous cell carcinoma without neoadjuvant chemotherapy. GSTP1 was related to malignant potential and may be a predictive marker of drug resistance in esophageal squamous cell carcinoma patients [143]. A previous study found a significant association between the variant GSTP1 Ala114Val genotype and increased risk of recurrence and death.…”

Section: Usefulness Of Gstp1-1 Enzymatic Activity In Some Pathologmentioning

confidence: 99%

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

et al. 2019

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Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. This review collects studies that propose GSTP1-1 as a useful biomarker in different fields of application. The most relevant studies are focused on GSTP1-1 as a biosensor to detect blood toxicity in patients affected by kidney diseases. In fact, this detoxifying enzyme is over-expressed in erythrocytes when unusual amounts of toxins are present in the body. Here we review articles concerning the level of GST in chronic kidney disease patients, in maintenance hemodialysis patients and to assess dialysis adequacy. GST is also over-expressed in autoimmune disease like scleroderma, and in kidney transplant patients and it may be used to check the efficiency of transplanted kidneys. The involvement of GSTP in the oxidative stress and in other human pathologies like cancer, liver and neurodegenerative diseases, and psychiatric disorders is also reported. Promising applications of e-GST discussed in the present review are its use for monitoring human subjects living in polluted areas and mammals for veterinary purpose.

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Glutathione S‐transferase Pi 1 is a valuable predictor for cancer drug resistance in esophageal squamous cell carcinoma

Cited by 16 publications

References 33 publications

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

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