Potential Role of GST-π in Lung Cancer Stem Cell Cisplatin Resistance

Wang, Wenjun; Wei, Jianping; Tu, Xiao-Yun; Ye, Xiaoqun

doi:10.1155/2021/9142364

Cited by 4 publications

(2 citation statements)

References 32 publications

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“…Once cells are stimulated by cytokines, radiative, oxidative, or other types o stress, GSTP1 dissociates from JNK, and the activated JNK mediates phosphorylation o c-Jun, a member of the activated protein-1 (AP-1) transcription complex. Phosphorylated c-Jun, in turn, regulates biological processes such as cell proliferation and apoptosis [59] It has been confirmed that GSTP1 is highly expressed in a variety of cancer cells [60][61][62][63] which is considered an essential mechanism of multidrug resistance to chemotherapeutic because suppression of JNK leads to the prevention of apoptosis. GSTA1 and GSTM1 can also form protein complexes with JNK in a mechanism similar to GSTP1, but their inhibi tory activity against JNK is rather weak [2,36].…”

Section: Jnk Signaling Pathwaymentioning

confidence: 99%

“…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 [63]. The mechanism of drug resistance may involve a variety of proteins.…”

Section: Gsts and Tumor Multidrug Resistancementioning

confidence: 99%

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Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

Lv,

Huang,

Huang

et al. 2023

Antioxidants

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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. In the past few decades, 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 in recent years, although the exact regulatory mechanisms remain to be elucidated. This review, firstly summarizes the roles of GSTs and their overexpression in the above-mentioned diseases with emphasis on the modulation of cell signaling pathways and protein functions. Secondly, specific GST inhibitors currently in pre-clinical development and in clinical stages are inventoried. Lastly, applications of GST inhibitors in targeting cell signaling pathways and intracellular biological processes are discussed, and the potential for disease treatment is prospected. Taken together, this review is expected to provide new insights into the interconnection between GST overexpression and human diseases, which may assist future drug discovery targeting GSTs.

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Section: Jnk Signaling Pathwaymentioning

confidence: 99%

Section: Gsts and Tumor Multidrug Resistancementioning

confidence: 99%

Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

Lv,

Huang,

Huang

et al. 2023

Antioxidants

View full text Add to dashboard Cite

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Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors

et al. 2023

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Glutathione S‐transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self‐renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin‐dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2‐related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization‐dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient‐derived organoids from an ALK‐translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long‐term control of LUAD through targeting CSCs.

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