Abstract

Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor formation and neo-angiogenesis in vivo. Depletion of cyclin D1 significantly radiosensitizes PCa cells by increasing the RT-induced DNA damages by affecting the NHEJ and HR pathways responsible of the DNA double-strand break repair. Following treatment of cells with RT the abundance of a biomarker of DNA damage, γ-H2AX, was dramatically increased in sh-cyclin D1 treated cells compared to shRNA control. Concordant with these observations DNA-PKcs-activation and RAD51-accumulation, part of the DNA double-strand break repair machinery, were reduced in shRNA-cyclin D1 treated cells compared to shRNA control. We further demonstrate the physical interaction between CCND1 with activated-ATM, -DNA-PKcs and RAD51 is enhanced by RT. Finally, siRNA-mediated silencing experiments indicated DNA-PKcs and RAD51 are downstream targets of CCND1-mediated PCa cells radioresistance. In summary, these observations suggest that CCND1 is a key mediator of PCa radioresistance and could represent a potential target for radioresistant hormone-resistant PCa.

Highlights

  • Prostate cancer (PCa) is the most commonly diagnosed male malignancy and the second leading cause of cancer death in men

  • Previous studies indicate that the response to Radiation therapy (RT) is different between androgen-dependent and androgen-independent prostate cancer (PCa) cells, indicating that molecular events mediated by androgen may function in radiosensitization and that androgen-independency may be associated with radiation resistance in PCa [3]

  • Several evidence show that PCa cells with an androgenindependent phenotype have higher biochemical failure rates after RT suggesting that androgen-independency may be associated with radiation resistance in PCa [3]

Read more

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed male malignancy and the second leading cause of cancer death in men. Previous studies indicate that the response to RT is different between androgen-dependent and androgen-independent PCa cells, indicating that molecular events mediated by androgen may function in radiosensitization and that androgen-independency may be associated with radiation resistance in PCa [3]. Epigenetic and molecular abnormalities have been associated with radiation resistance in PCa [4], the molecular mechanisms responsible of radiation resistance and relationship with androgen-independent PCa phenotype remains unknown. Understanding these phenomena could lead to new molecular targets and more directed therapy able to improve the RT efficiency

Methods
Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.