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

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          Based on its role in angiogenesis and apoptosis, the inhibition of NFκB 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 NFκB, thus we evaluated its effects on cancer growth.


          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.


          In vitro, adenovirus mediated GRK5-RH overexpression (AdGRK5-NT) in human tumor cells (KAT-4) induces IκB accumulation and inhibits NFκB 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 NFκB activity, an increase of IκB 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.


          Our data suggest that GRK5-RH inhibition of NFκB is a novel and effective anti-tumoral strategy and TAT-RH could be an useful tool in the fighting of cancer.

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          Most cited references 40

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          NF-kappaB in cancer: from innocent bystander to major culprit.

          Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.
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            TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB.

            Many cells are resistant to stimuli that can induce apoptosis, but the mechanisms involved are not fully understood. The activation of the transcription factor nuclear factor-kappa B (NF-kappaB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound), was found to protect from cell killing. Inhibition of NF-kappaB nuclear translocation enhanced apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-kappaB. These results provide a mechanism of cellular resistance to killing by some apoptotic reagents, offer insight into a new role for NF-kappaB, and have potential for improvement of the efficacy of cancer therapies.
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              Series introduction: the transcription factor NF-kappaB and human disease.


                Author and article information

                Mol Cancer
                Molecular Cancer
                BioMed Central
                9 November 2009
                : 8
                : 97
                [1 ]Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italia
                [2 ]CEINGE-Biotecnologie Avanzate, Napoli, Italia
                [3 ]Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Napoli, Italia
                Copyright ©2009 Sorriento et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


                Oncology & Radiotherapy


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