title: Inhibition of DNA-dependent protein kinase promotes ultrasound-induced cell death including apoptosis in human leukemia cells.
abstract: Ultrasound (US) has been shown to induce cell death in cancer cells; however, the underlying mechanism remains elusive. Here, we report a set of novel findings on the molecular mechanism. We found that Akt (also known as protein kinase B), a substrate of DNA-dependent protein kinase (DNA-PK), was phosphorylated in U937 cells nullified with p53 or Molt-4 cells artificially abrogated with p53 after US exposure. On the contrary, Akt phosphorylation was transiently down-regulated then recovered in Molt-4 cells harboring wild-type p53 in US-exposed cells, possibly due to a mutual regulation between p53 and Akt. Inhibition of ataxia-telangiectasia mutated (ATM) or DNA-PK revealed that DNA-PK, rather than ATM, was preferentially involved in Akt phosphorylation and cell survival after US-exposure in all cell lines. These results indicate that DNA-PK plays a protective role against US-induced cell death regardless of p53 phenotype. In conclusion, our findings provide the first delineation of the role of DNA-PK in US-induced cell death and suggest that targeting DNA-PK might be a promising strategy to augment cancer eradication by US.
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine Pharmaceutical Sciences, University of Toyama, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Yoshisada
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Mariame Ali
authors.initials: MA
authors.lastname: Hassan
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tabuchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Morita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology; D020298:U937 Cells; D014464:Ultrasonic Therapy
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt