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

Authors:
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Alfonso Campanile
Alfonso Campanile
Ospedale Maggiore Policlinico
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
Eleonora Leggiero
Eleonora Leggiero
University of Naples Federico II
Italy
Lucio Pastore
Lucio Pastore
University of Naples "Federico II"
Italy
Bruno Trimarco
Bruno Trimarco
Federico II University
Napoli | Italy
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy

Mol Cancer 2009 Nov 9;8:97. Epub 2009 Nov 9.

Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italia.

Background: Based on its role in angiogenesis and apoptosis, the inhibition of NFkappaB 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 NFkappaB, 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 IkappaB accumulation and inhibits NFkappaB 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 NFkappaB activity, an increase of IkappaB 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 NFkappaB 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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Source
http://dx.doi.org/10.1186/1476-4598-8-97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780391PMC

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November 2009
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