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Journal of Cancer Research and Clinical Oncology

, Volume 144, Issue 9, pp 1685–1699 | Cite as

Disruption of MEK/ERK/c-Myc signaling radiosensitizes prostate cancer cells in vitro and in vivo

  • Carmela Ciccarelli
  • Agnese Di Rocco
  • Giovanni Luca Gravina
  • Annunziata Mauro
  • Claudio Festuccia
  • Andrea Del Fattore
  • Paolo Berardinelli
  • Francesca De Felice
  • Daniela Musio
  • Marina Bouché
  • Vincenzo Tombolini
  • Bianca Maria Zani
  • Francesco Marampon
Original Article – Cancer Research

Abstract

Purpose

Prostate cancer (PCa) cell radioresistance causes the failure of radiation therapy (RT) in localized or locally advanced disease. The aberrant accumulation of c-Myc oncoprotein, known to promote PCa onset and progression, may be due to the control of gene transcription and/or MEK/ERK-regulated protein stabilization. Here, we investigated the role of MEK/ERK signaling in PCa.

Methods

LnCAP, 22Rv1, DU145, and PC3 PCa cell lines were used in in vitro and in vivo experiments. U0126, trametinib MEK/ERK inhibitors, and c-Myc shRNAs were used. Radiation was delivered using an x-6 MV photon linear accelerator. U0126 in vivo activity alone or in combination with irradiation was determined in murine xenografts.

Results

Inhibition of MEK/ERK signaling down-regulated c-Myc protein in PCa cell lines to varying extents by affecting expression of RNA and protein, which in turn determined radiosensitization in in vitro and in vivo xenograft models of PCa cells. The crucial role played by c-Myc in the MEK/ERK pathways was demonstrated in 22Rv1 cells by the silencing of c-Myc by means of short hairpin mRNA, which yielded effects resembling the targeting of MEK/ERK signaling. The clinically approved compound trametinib used in vitro yielded the same effects as U0126 on growth and C-Myc expression. Notably, U0126 and trametinib induced a drastic down-regulation of BMX, which is known to prevent apoptosis in cancer cells.

Conclusions

The results of our study suggest that signal transduction-based therapy can, by disrupting the MEK/ERK/c-Myc axis, reduce human PCa radioresistance caused by increased c-Myc expression in vivo and in vitro and restores apoptosis signals.

Keywords

Prostate cancer C-Myc ERKs U0126 Radiotherapy Radioresistance 

Notes

Acknowledgements

We are grateful to the Umberto Veronesi Foundation for awarding a post-doctoral fellowship to Francesco Marampon for the year 2018. This project is funded in part by the MIUR to BMZ, by the University of L’Aquila (B.M. Zani) and by the “Cassa Edile di Roma e Provincia” (B.M. Zani). We are grateful to Lewis Baker for revising the English in the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no affiliations to disclose, including any of a financial nature, that they consider to be relevant or related to the subject matter discussed.

Ethical standards

Nude mice were maintained according to the guidelines established by our institution (University of L’Aquila, Medical School and Science and Technology School Board Regulations, in compliance with the Italian government regulation n.116 of January 27, 1992 for the use of laboratory animals).

Supplementary material

432_2018_2696_MOESM1_ESM.ppt (112 kb)
Supplementary material 1 (PPT 111 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Carmela Ciccarelli
    • 1
  • Agnese Di Rocco
    • 1
  • Giovanni Luca Gravina
    • 1
  • Annunziata Mauro
    • 2
  • Claudio Festuccia
    • 1
  • Andrea Del Fattore
    • 3
  • Paolo Berardinelli
    • 2
  • Francesca De Felice
    • 4
  • Daniela Musio
    • 4
  • Marina Bouché
    • 5
  • Vincenzo Tombolini
    • 5
  • Bianca Maria Zani
    • 1
  • Francesco Marampon
    • 1
    • 5
  1. 1.Department of Biotechnological and Applied Clinical SciencesUniversity of L’AquilaL’AquilaItaly
  2. 2.Unit of Basic and Applied Biosciences, Faculty of Bioscience and Technology for Food, Agriculture and EnvironmentUniversity of TeramoTeramoItaly
  3. 3.Multi-Factorial Disease and Complex Phenotype Research AreaBambino Gesù Children’s Hospital, IRCCSRomeItaly
  4. 4.Division of Radiotherapy, Department of Radiology, Radiation Oncology and Human Pathology“Sapienza” University of RomeRomeItaly
  5. 5.Unit of Histology, Department of Anatomy, Histology, Forensic Medicine and OrthopedicsSapienza University of RomeRomeItaly

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