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Cited by 1,353Glutathione Transferases and PolymorphismsPharmacogenetics and Drug MetabolismDrug Transport and Resistance Mechanisms

The role of glutathione-S-transferase in anti-cancer drug resistance

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Townsend, Danyelle M, Tew, Kenneth D·2003·Oncogene
DOI 10.1038/sj.onc.1206940PMC PMC6361125
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Abstract

Glutathione-S-transferases (GSTs) are a family of Phase II detoxification enzymes that catalyse the conjugation of glutathione (GSH) to a wide variety of endogenous and exogenous electrophilic compounds. GSTs are divided into two distinct super-family members: the membrane-bound microsomal and cytosolic family members. Microsomal GSTs are structurally distinct from the cytosolic in that they homo- and heterotrimerize rather than dimerize to form a single active site. Microsomal GSTs play a key role in the endogenous metabolism of leukotrienes and prostaglandins. Human cytosolic GSTs are highly polymorphic and can be divided into six classes: alpha, mu, omega, pi, theta, and zeta. The pi and mu classes of GSTs play a regulatory role in the mitogen-activated protein (MAP) kinase pathway that participates in cellular survival and death signals via protein : protein interactions with c-Jun N-terminal kinase 1 (JNK1) and ASK1 (apoptosis signal-regulating kinase). JNK and ASK1 are activated in response to cellular stress. GSTs have been implicated in the development of resistance toward chemotherapy agents. It is plausible that GSTs serve two distinct roles in the development of drug resistance via direct detoxification as well as acting as an inhibitor of the MAP kinase pathway. The link between GSTs and the MAP kinase pathway provides a rationale as to why in many cases the drugs used to select for resistance are neither subject to conjugation with GSH, nor substrates for GSTs. GSTs have emerged as a promising therapeutic target because specific isozymes are overexpressed in a wide variety of tumors and may play a role in the etiology of other diseases, including neurodegenerative diseases, multiple sclerosis, and asthma. Some of the therapeutic strategies so far employed are described in this review.

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  • Many GST protein family members act as tumor promoters by influencing reactive oxygen species (ROS).

    “Many GST protein family members act as tumor promoters by influencing reactive oxygen species (ROS) (51–56).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [52]

    Table 1 (page unavailable) lists products generated by reactive oxygen species as substrates of α and μ GSTs, and the discussion of GSTs as regulators of the MAP kinase pathway links GSTπ and GSTμ to cell-survival signaling. The paper does not say that many GST family members promote tumors by influencing ROS; it describes elevated GST expression in tumors and says GSTπ may be either a cause or an effect of transformation. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Townsend, D. M., & Tew, K. D.
Affiliations
Fox Chase Cancer Center (US)
Corresponding author
Tew, Kenneth D
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2003-10-20
Volume
22
Issue
47
Pages
7369-7375
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/sj.onc.1206940
PMC
PMC6361125
OpenAlex
W2013485244
Cited by
1,353
References
0
Citations by year
2026: 44 · 2025: 70 · 2024: 62 · 2023: 80 · 2022: 77 · 2021: 98 · 2020: 68 · 2019: 64 · 2018: 73 · 2017: 70 · 2016: 70 · 2015: 78 · 2014: 76 · 2013: 56 · 2012: 57
FWCI
2.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (T32CA119945, R01CA085660)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
glutathione S-transferase, drug resistance, chemoresistance, glutathione conjugation, detoxification enzymes, MAPK signaling, JNK1, ASK1, GST isozymes, GST polymorphisms, therapeutic target, neurodegenerative diseases, multiple sclerosis, asthma
MeSH terms
Antineoplastic Agents, Enzyme Inhibitors, Glutathione Transferase, Humans, Inactivation, Metabolic, Neoplasms, Drug Resistance, Neoplasm, MAP Kinase Signaling System

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