Thioredoxin, thioredoxin reductase and tumour necrosis factor-α expression in melanoma cells : correlation to resistance against cytotoxic attack

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Abstract

Although malignant melanomas are often associated with cytotoxic lymphocyte infiltration, these cells are largely ineffective in inducing tumour cell kill, indicating that the melanoma cells have protective mechanisms. These mechanisms are not fully understood, but cytokines and redox-active antioxidant proteins such as catalase, superoxide dismutase, thioredoxin (Trx) and Trx reductase (TrxR) present in the tumour cells constitute part of this protection. In this study firstly we investigated the constitutive intracellular expression of Trx, TrxR, the cytokines interleukin (IL)-1α, IL1β, IL2, IL4, IL6, IL8, IL10, tumour necrosis factor-α (TNFα) and interferon-γ (IFNγ) in normal melanocytes and ten primary and metastatic malignant melanoma cell lines. Secondly, we analysed whether redox stimulation by Trx alone or in combination with the phorbol ester PMA affected the expression and release of TNFα. Thirdly, we explored the possible correlation between Trx/TrxR expression and resistance to exogenous TNFα. All the cultured cells showed intracellular overexpression of Trx and TrxR, which was not always the case for melanoma cellsin vivo(tissue sections). The predominant intracellular cytokines found were TNFα, IL1α and IL1β. In spite of its presence in the Golgi apparatus, none of the cell lines secreted TNFα constitutively, and only one melanoma, FM3, released detectable amounts after stimulation. In contrast, U-937 monocyte control cells released high amounts of TNFα on identical stimulation. All the melanoma cell lines were relatively resistant against exogenous TNFα, and there was a significant correlation (P< 0.01) between intracellular Trx/TrxR expression and TNFα resistance (IC50). In conclusion, Trx and TrxR, as well as TNFα, IL1α and IL1β, were highly expressed in cultured normal skin melanocytes and malignant melanoma cell lines. In contrast to U-937 monocytic cells, TNFα showed a secretory block in these cells, suggesting a cytoprotective and possible autocrine role for TNFα. The intracellular expression of Trx and TrxR together with endogenous TNFα was correlated with the resistance to TNFα-induced cytotoxicity.

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