title: Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines.
abstract: Both Aurora-A and -B kinases have been implicated in tumorigenesis; and as such, they represent an attractive therapeutic target. Recent studies found that Aurora-A is a downstream target of mitogen-activated protein kinase 1/ERK2, while Aurora-B has been found to be a prognostic/predictive therapeutic target for epithelial cancer. In a wide range of human cancers, the Ras/Raf/MEK/ERK/MAP kinase pathway is enhanced and the cellular response to growth signals is known to increase. The purpose of this study was to investigate whether the MEK/ERK cascade regulates tumorigenic signaling and radioresistance via the Aurora-B-mediated pathway in a panel of gynecological cancer cell lines. Exponentially growing human endometrial (Ishikawa), cervical (HeLa), cervical (CASKI) and vulva (SiHa) cancer cells were used in culture treated with either control or MEK/ERK inhibitor or AZD1152 before and after irradiation. Western blotting, ERK1/2 siRNA transfection, growth assay in modified monolayer, Annexin V and migration/invasion assays were performed. The specific MEK/ERK inhibitor U0126 decreased the tumorigenic potential and improved the radiation response in all cellular models. The modulation of radioresponse upon U0126 treatment positively correlated with the inhibition of phospho-ERKs and the reduction of Aurora-B kinase expression. In addition, upon U0126 treatment DNA-PKcs protein expression was found to be downregulated, indicating that the improved radiation response may be caused by decreased DNA double-strand damage repair mechanisms. The knockdown of ERK by siRNA confirmed the MEK/ERK-dependent Aurora-B kinase expression. The use of AZD1152, a selective Aurora-B inhibitor, counteracted tumorigenic potential and radioresistance phenotype by highly increasing apoptotic mechanisms in all gynecological cancer cell lines used. Evidence from our experiments show that tumorigenic potential and radiation response in gynecological cancer cells may ensue from a MEK/ERK or Aurora-B inhibition. Together with the close correlation of MEK/ERK and Aurora-B protein expression, this study underlines the potential role of a MEK/ERK/Aurora-B axis whose interruption recovers the antitumor effects of radiotherapy.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy and Radiobiology Laboratory, San Salvatore Hospital, University of L'Aquila, I-67100 L'Aquila, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marampon
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Valdimir M
authors.initials: VM
authors.lastname: Popov
authors.forename: Luca
authors.initials: L
authors.lastname: Scarsella
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.forename: Maria Emilia
authors.initials: ME
authors.lastname: La Verghetta
authors.forename: Silvia
authors.initials: S
authors.lastname: Parente
authors.forename: Manuela
authors.initials: M
authors.lastname: Cerasani
authors.forename: Gemma
authors.initials: G
authors.lastname: Bruera
authors.forename: Corrado
authors.initials: C
authors.lastname: Ficorella
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tombolini
authors.forename: Ernesto
authors.initials: E
authors.lastname: Di Cesare
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Zani
mesh_terms: D064107:Aurora Kinase B / Q000235:genetics*; D002070:Butadienes / Q000494:pharmacology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D005260:Female; D005833:Genital Neoplasms, Female / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011379:Prognosis; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D064107:Aurora Kinase B