title: High expression of GCLC is associated with malignant melanoma of low oxidative phenotype and predicts a better prognosis.
abstract: Reactive oxygen species (ROS) are strongly implicated in melanoma development, and treatment with antioxidants has shown efficacy in suppressing malignant transition and progression. Here, we investigated the significance of the glutamate-L: -cysteine ligase catalytic subunit (GCLC) expression, a key regulator of glutathione synthesis, for malignant melanoma. A large set of melanoma cell lines (n = 36) was analyzed, and higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation. Moreover, treatment with the antioxidant N-acetylcysteine efficiently reduced the growth speed of several investigated malignant cells. In addition GCLC expression was significantly linked to a prominent set of cellular antioxidants, accounting for the observed lower basal levels of oxidative stress and higher antioxidative capacity. Key attributes defining the malignant phenotype of melanoma cells including survival, invasiveness, and switch from E-cadherin to N-cadherin expression were more prominent in cells with lower GCLC expression. Our findings were further corroborated by observations in Rag2(-/-)γc(-/-)mice, in which melanoma cells with lower GCLC expression depicted a dramatically stronger tumor growth. Furthermore, prognostic significance of GCLC expression was investigated in patients (n = 28) with advanced malignant melanoma. High tumor immunoreactivity for GCLC was a significant determinant for better 5-year overall survival. Conclusively, we show for the first time that GCLC may serve a dual role, as a surrogate marker for cellular redox state as well as malignant potential of melanoma cells. These promising results regarding its prognostic significance as well as its potential as a pharmacological target require further in-depth investigations.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. dimitrios.mougiakakos@uk-erlangen.de
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
authors.forename: Riki
authors.initials: R
authors.lastname: Okita
authors.forename: Takashi
authors.initials: T
authors.lastname: Ando
authors.forename: Christoph
authors.initials: C
authors.lastname: Dürr
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.forename: Jiro
authors.initials: J
authors.lastname: Ichikawa
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.forename: C Christian
authors.initials: CC
authors.lastname: Johansson
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species; D005721:Glutamate-Cysteine Ligase; D000111:Acetylcysteine