Nuclear localization of glutamate-cysteine ligase is associated with proliferation in head and neck squamous cell carcinoma

Abstract

Glutathione (GSH) is the keystone of the cellular response toward oxidative stress. Elevated GSH content correlates with increased resistance to chemotherapy and radiotherapy of head and neck (HN) tumors. The purpose of the present cross-sectional study was to evaluate whether the expression of glutamate-cysteine ligase (GCL) accounts for the increased GSH availability observed in HN squamous cell carcinoma (SCC). For that purpose, the messenger (m)RNA levels of the modifier (M) and catalytic (C) subunits of GCL and its putative regulators (namely, nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) were monitored in 35 surgical resections of untreated HNSCC. The localization of GCLM was evaluated using in situ hybridization and immunohistochemistry. GCLM expression was significantly increased in tumor samples, compared with normal mucosa, both at the mRNA and protein level (P=0.029), but the pathway of GCLM activation remains to be elucidated. Protein expression of GCLM was detected in the cytoplasm and nucleus. GCLM and the proliferation marker Ki-67 displayed a similar distribution, being both mainly expressed at the periphery of tumor lobules. The present study reported increased expression of GCL and the rate-limiting enzyme of GSH synthesis, within HNSCC. The nuclear localization of GCLM and the concomitant expression of Ki-67 suggested that the localization of GSH synthesis contributes to the protection against oxidative stress within hotspots of cell proliferation.

Prognostic Significance of Glutathione Peroxidase Levels (GPx1) in Head and Neck Cancers

“…Therefore, in line with our previous studies pointing at the role of glutathione and associated enzymes as potential biological markers ( 5 , 6 ), we have investigated relationships between GPx1 and prognosis of head and neck squamous cell carcinoma (HNSCC).…”

Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation

“…With regard to GSH biosynthesis, many tumours show an enhanced expression of GCLC and GCLM. Indeed, the expression/activity of GCLC and/or GCLM is high in patients with lung cancer, squamous cell carcinoma and renal cell carcinoma [ 222 , 223 , 224 ] and can be associated with chemoresistance condition [ 222 , 225 ].…”