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.