A new synthetic protein, TAT-RH, inhibits tumor growth through the regulation of NFκB activity

Background: Based on its role in angiogenesis and apoptosis, the inhibition of NF kappa B activity is considered an effective treatment for cancer, hampered by the lack of selective and safe inhibitors. We recently demonstrated that the RH domain of GRK5 (GRK5-RH) inhibits NF kappa B, thus we evaluated its effects on cancer growth. Methods: The role of GRK5-RH on tumor growth was assessed in a human cancer cell line (KAT-4). RH overexpression was induced by adenovirus mediated gene transfer; alternatively we administered a synthetic protein reproducing the RH domain of GRK5 (TAT-RH), actively transported into the cells. Results: In vitro, adenovirus mediated GRK5-RH overexpression (AdGRK5-NT) in human tumor cells (KAT-4) induces I kappa B accumulation and inhibits NF kappa B transcriptional activity leading to apoptotic events. In BALB/c nude mice harboring KAT-4 induced neoplasias, intra-tumor delivery of AdGRK5-NT reduces in a dose-dependent fashion tumor growth, with the highest doses completely inhibiting it. This phenomenon is paralleled by a decrease of NF kappa B activity, an increase of I kappa B levels and apoptotic events. To move towards a pharmacological setup, we synthesized the TAT-RH protein. In cultured KAT-4 cells, different dosages of TAT-RH reduced cell survival and increased apoptosis. In BALB/c mice, the anti-proliferative effects of TAT-RH appear to be dose-dependent and highest dose completely inhibits tumor growth. Conclusion: Our data suggest that GRK5-RH inhibition of NF kappa B is a novel and effective anti-tumoral strategy and TAT-RH could be an useful tool in the fighting of cancer.