Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines

  • Authors:
    • Francesco Marampon
    • Giovanni Luca Gravina
    • Valdimir M. Popov
    • Luca Scarsella
    • Claudio Festuccia
    • Maria Emilia La Verghetta
    • Silvia Parente
    • Manuela Cerasani
    • Gemma Bruera
    • Corrado Ficorella
    • Enrico Ricevuto
    • Vincenzo Tombolini
    • Ernesto Di Cesare
    • Bianca Maria Zani
  • View Affiliations

  • Published online on: November 5, 2013     https://doi.org/10.3892/ijo.2013.2167
  • Pages: 285-294
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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.
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2014-January
Volume 44 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Marampon F, Gravina GL, Popov VM, Scarsella L, Festuccia C, La Verghetta ME, Parente S, Cerasani M, Bruera G, Ficorella C, Ficorella C, et al: Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines. Int J Oncol 44: 285-294, 2014
APA
Marampon, F., Gravina, G.L., Popov, V.M., Scarsella, L., Festuccia, C., La Verghetta, M.E. ... Zani, B.M. (2014). Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines. International Journal of Oncology, 44, 285-294. https://doi.org/10.3892/ijo.2013.2167
MLA
Marampon, F., Gravina, G. L., Popov, V. M., Scarsella, L., Festuccia, C., La Verghetta, M. E., Parente, S., Cerasani, M., Bruera, G., Ficorella, C., Ricevuto, E., Tombolini, V., Di Cesare, E., Zani, B. M."Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines". International Journal of Oncology 44.1 (2014): 285-294.
Chicago
Marampon, F., Gravina, G. L., Popov, V. M., Scarsella, L., Festuccia, C., La Verghetta, M. E., Parente, S., Cerasani, M., Bruera, G., Ficorella, C., Ricevuto, E., Tombolini, V., Di Cesare, E., Zani, B. M."Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines". International Journal of Oncology 44, no. 1 (2014): 285-294. https://doi.org/10.3892/ijo.2013.2167