Background: 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. 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 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 dosedependent and highest dose completely inhibits tumor growth. Conclusion: Our data suggest that GRK5-RH inhibition of NFκB is a novel and effective antitumoral strategy and TAT-RH could be an useful tool in the fighting of cancer.

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

Sorriento D;SANTULLI, GAETANO;LEGGIERO, ELEONORA;PASTORE, LUCIO;TRIMARCO, BRUNO;IACCARINO, GUIDO
2009

Abstract

Background: 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. 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 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 dosedependent and highest dose completely inhibits tumor growth. Conclusion: Our data suggest that GRK5-RH inhibition of NFκB is a novel and effective antitumoral strategy and TAT-RH could be an useful tool in the fighting of cancer.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/371431
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