Deregolazione di NF-kB nel carcinoma prostatico: identificazione di target genes come potenziali bersagli terapeutici

NF-κB family represents a group of inducible transcription factors, which regulates a large number of genes involved in inflammation, immunity, cell growth, proliferation, and survival. Because so many crucial processes are regulated by these factors, is not surprising that dysregulation of this pathway is involved in the pathogenesis of several disease such as inflammatory conditions, autoimmunity, and cancer. Indeed, constitutive and enhanced activation of NF-κB factors is a hallmark of many types of tumours including lymphoid malignancies, hepatocellular carcinoma, breast cancer, and colorectal cancer. Since NF-κB target genes include regulators and inhibitors of apoptosis, and other factors that promote resistance to chemotherapeutic drugs used in conventional anti-cancer therapies, in recent years, many efforts have been made to develop inhibitory drugs that specifically target this pathway. However, although offering great clinical potential, inhibition of NF-κB in vivo can result in severe side effects, therefore, the main goal is to find a safe way to specifically target this pathway without interfering with general homeostasis. In this respect, a potential target gene is GADD45B. Indeed, the protein GADD45B is induced by NF-κB and plays a protective role towards JNK pathway-induced apoptosis. The ability of GADD45B in inhibiting JNK activity is due to its ability to bind and block the upstream kinase MKK7 thus preventing JNK activation. Tornatore et al. have shown the pro-survival role of GADD45B in multiple myeloma and effective targeting of this pathway, without significant side effects, using the D-tripeptide (DTP3), which interfere with GADD45B-MKK7 complex thus resulting in JNK-induced apoptosis. The aim of this project was to assess the NF-κB expression in human prostate carcinoma and its activation status in prostate carcinoma cell models, and to determinate the role of NF-κB-dependent GADD45B anti-apoptotic gene in prostate carcinoma in order to evaluate the inhibition of its activity as a potential therapeutic strategy for this tumor.