Abstract
γ-Glutamylcyclotransferase (GGCT), which is one of the major enzymes involved in glutathione metabolism, is upregulated in a wide range of cancers—glioma, breast, lung, esophageal, gastric, colorectal, urinary bladder, prostate, cervical, ovarian cancers and osteosarcoma—and promotes cancer progression; its depletion leads to the suppression of proliferation, invasion, and migration of cancer cells. It has been demonstrated that the suppression or inhibition of GGCT has an antitumor effect in cancer-bearing xenograft mice. Based on these observations, GGCT is now recognized as a promising therapeutic target in various cancers. This review summarizes recent advances on the mechanisms of the antitumor activity of GGCT inhibition.
Highlights
GGCT Upregulation in CancerGromov et al performed a large-scale proteome analysis in 123 cases of breast cancer and found that GGCT was highly expressed in neoplastic mammary tissues [7]
Introduction γGlutamylcyclotransferase (GGCT, 188 amino acids, 21 kDa) is an enzyme involved in glutathione metabolism [1], and has recently been described to be overexpressed in a variety of cancers and as a critical player in cancer cell proliferation [2]
These findings demonstrated that induction of cellular senescence mediated by the upregulation of CDK inhibitors was a major event underlying the antiproliferative effect caused by GGCT depletion in cancer cells
Summary
Gromov et al performed a large-scale proteome analysis in 123 cases of breast cancer and found that GGCT was highly expressed in neoplastic mammary tissues [7] They reported on the association between the expression of GGCT and patient outcome, and showed that patients with high GGCT expression had a poor prognosis. Li et al reported that GGCT was upregulated in ovarian cancers and associated with advanced FIGO (International Federation of Gynecology and Obstetrics) stage, lymph node metastases, and ascitic fluid volume in high-grade serous ovarian cancers (HGSCs) [16] They observed that GGCT upregulation was related to poor survival in HGSCs. They observed that GGCT upregulation was related to poor survival in HGSCs Their multivariate analysis showed that FIGO stage, lymph node metastasis and GGCT expression were independent prognostic factors for overall and progression free survival. The upregulation of GGCT has been reported in a wide range of cancer cell lines including breast, ovarian, cervical, lung, urinary bladder, prostate, colon cancers, osteosarcoma, and glioma cells. GGCT might not be directly involved in malignant transformation, but in other events that lead to the malignant phenotype
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