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.

ERK1/2 promoted proliferation and inhibited apoptosis of human cervical cancer cells and regulated the expression of c-Fos and c-Jun proteins

“…In this study, the results indicated that down-regulating ERK1/2 with U0126 inhibited Hela and C33A cells proliferation, induced cell apoptosis, arrested the cell cycle in G0/G1 stage, and decreased the proportions of G2/M stages. It was consistent with the previous finding that U0126 decreased the tumorigenic potential of cervical cancer and improved the radiation response in all cellular models [25]. However, an opposite result was observed by a recent study.…”

Human omental adipose-derived mesenchymal stem cell-conditioned medium alters the proteomic profile of epithelial ovarian cancer cell lines in vitro

“…Mutational activation of the Ras–Raf–MEK–ERK kinase pathway is frequently observed in a wide range of human cancers, including gynecological cancer, and PHB has been demonstrated to be mandatory for this signaling pathway 15,16. As listed in Table 2, PHB was involved in tumor progression in ovarian cancer 17,18.…”

Adenosine: An endogenous mediator in the pathogenesis of gynecological cancer

“…(Fredholm, IJzerman, et al, 2001;Schulte & Fredholm, 2003). With respect to gynecological cancer, using U0126, an inhibitor of MEK/ERK or AZD1152, an inhibitor of Aurora-B kinase, oncogenic serine/threonine kinase positively affected by Ras/Raf/MEK/ERKs pathway, declined tumorigenic potential and radioresistance phenotype through enhancing apoptotic mechanisms in diverse gynecological cancer cell lines including Ishikawa, HeLa, CASKI, and SiHa cells (Marampon et al, 2014), suggesting that inhibition of Ras/Raf/MEK/ERKs pathway could be a novel therapeutic procedures for gynecological cancer. Furthermore, it has been shown that nucleoside transporters could also regulate adenosine concentrations in gynecological cancers.…”