Abstract
γ-Glutamyltransferase (GGT), a membrane-bound enzyme, contributes to the metabolism of glutathione (GSH), which plays a critical physiological role in protecting cells against oxidative stress. GGT has been proposed as a biomarker of carcinogenesis and tumor progression given that GGT activity is important during both the promotion and invasion phases in cancer cells. Moreover, GGT expression is reportedly related to drug-resistance possibly because a wide range of drugs are conjugated with GSH, the availability of which is influenced by GGT activity. While serum GGT activity is commonly used as a quick, inexpensive, yet reliable means of assessing liver function, recent epidemiological studies have shown that it may also be an indicator of an increased risk of prostate cancer development. Moreover, elevated serum GGT is reportedly an adverse prognostic predictor in patients with urologic neoplasms, including renal cell carcinoma, prostate cancer, and urothelial carcinoma, although the background mechanisms have still not been well-characterized. The present review article summarizes the possible role of GGT in cancer cells and focuses on evidence evaluation through a systematic review of the latest literature on the prognostic role of serum GGT in patients with genitourinary cancer.
Highlights
Introduction γ-Glutamyltransferase (GGT) is one of the enzymes involved in the γ-glutamyl cycle, which contributes to the synthesis and degradation of glutathione (GSH) [1]
In addition to being used as a hepatobiliary biomarker that is especially sensitive to excessive alcohol consumption [4], elevated serum GGT has been shown to be an adverse prognostic factor in patients with life-threatening diseases
Despite the objective antitumor activity observed in some trials, acivicin failed to be approved for clinical use because of the potential for severe toxicity, such as lethal myelosuppression and neurotoxicity, the causes of these adverse events were not clearly known at the time
Summary
There are at least eight potential full-length GGT family proteins, including GGT1, GGT2, GGT3P, GGT4P, GGT5, GGT6, GGT7, and GGT8P [15]. GGT1 and GGT5 are the only two enzymes that have been shown to be catalytically active [15,16] Immunolabelling of these closely related enzymes in human tissues has revealed different expression patterns in different organs or even within the same tissue (e.g., GGT1 is expressed on the apical surface of the renal proximal tubules whereas GGT5 is expressed in the interstitial cells of the kidney), resulting in access to different substrates [17]. Their enzymatic activities are not at the same level according to a previous kinetic analysis, which demonstrated that GGT1 is able to cleave GSH approximately 46 times faster than GGT5 [18]. The active site of human GGT1 was identified as Thr-381, which can be blocked by competitive inhibitors, including acivicin, azaserine, and 6-diazo-5-oxonorleucine, all of which are glutamate analogs [28]
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