NO-CANCER

Protein S-Nitrosylation in Inflammation and Cancer

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 Obiettivo del progetto (Objective)

'Chronic inflammation represents a major pathologic basis for many human cancers. Nitric oxide (NO) production is a hallmark of inflammation, and may play a significant role in inflammation-associated cancers. S-nitrosylation, the covalent attachment of an NO group to the thiol side chain of cysteine is a common mechanism for dynamic, post-translational regulation of most or all main classes of protein. Indeed, protein S-nitrosylation and denitrosylation have emerged as integral components of signal transduction pathways, and accumulating evidence suggests that deregulated S-nitrosylation contributes to a range of human pathologies. Yet, the involvement of protein S-nitrosylation/denitrosylation in inflammation-related cancer remains unclear. To elucidate the role of protein S-nitrosylation in inflammation-associated cancer we will employ models of lung cancer, where we will characterize the S-nitrosylated proteome, investigate denitrosylation mechanisms, and study the redox regulation of central mediators of inflammation. We focus on three areas of research: (1) advanced redox proteomics for the identification S-nitrosylated proteins in lung tumour cells and in lung macrophages; (2) characterization of the regulation by S-nitrosylation of key inflammatory mediators, particularly, the inflammasome; (3) investigation of mechanisms and consequences of protein denitrosylation in lung cancer cells.'

Introduzione (Teaser)

A European project was set up to find an association between protein modifications, inflammation and cancer. The results unveil novel mechanisms implicated in cancer development and could be used to design new therapies.

Descrizione progetto (Article)

Chronic inflammation is the underlying cause for many diseases including cancer and is characterised by nitric oxide (NO) production. The covalent attachment of an NO group to the cysteine residues on proteins is known as S-nitrosylation and constitutes a common post-translational mechanism. Its implication in signalling pathways is well established and deregulated S-nitrosylation is believed to be behind many pathologies.

To shed light on the hypothesis of deregulated protein S-nitrosylation in cancer, scientists on the EU-funded project 'Protein S-nitrosylation in inflammation and cancer' (NO-CANCER) looked at modified proteins in lung cancer cells. They also explored S-nitrosylated mediators of inflammation and set out to delineate the underlying mechanisms.

The scientific activities of the NO-CANCER project were based on the oxidoreductase enzyme thioredoxin (Trx), which physiologically acts to denitrosylate proteins. Researchers performed a proteomics analysis of Trx targets in macrophages and identified over 500 putative proteins. These proteins were implicated in a wide range of cellular pathways and processes, including protein folding, cell division and proliferation.

Several key inflammatory mediators (STAT3, MEK1 and iNOS) were also found to be regulated by reversible S-nitrosylation, underscoring the role of Trx-mediated denitrosylation in NO signalling. Inhibition of Trx function showed an overall anti-inflammatory impact by affecting pro-inflammatory proteins such as IL-1.

Taken together, the work of the NO-CANCER study discloses a novel role for protein nitrosylation in inflammation. The findings also lay the foundation for exploring this post-translational modification as a means of regulating protein function.