Loss of PDE4D7 expression promotes androgen independence, neuroendocrine differentiation, and alterations in DNA repair: implications for therapeutic strategies (original) (raw)
Gulliver, Chloe, Huss, Sebastian, Semjonow, Axel, Baillie, George S. 
ORCID: https://orcid.org/0000-0003-2469-6316 and Hoffmann, Ralf(2023) Loss of PDE4D7 expression promotes androgen independence, neuroendocrine differentiation, and alterations in DNA repair: implications for therapeutic strategies.British Journal of Cancer, 129(9), pp. 1462-1476. (doi: 10.1038/s41416-023-02417-5) (PMID:37740039) (PMCID:PMC10628190)
Abstract
Background: Androgen signalling remains the seminal therapeutic approach for the management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells. Methods: Using shRNA-mediated PDE4D7 knockdown in LNCaP cells and downstream analysis via RNA sequencing and phenotypic assays, we replicate clinical observations that diminished PDE4D7 expression promotes an aggressive prostate cancer phenotype. Results: Our study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. In addition, we demonstrate that PDE4D7 loss affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors. Conclusion: Reinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.
| Item Type: | Articles |
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| Additional Information: | We acknowledge the support provided by the University of Glasgow MVLS Doctoral Training Programme award to Chloe Gulliver. This project was supported by the framework of CTMM (The Center for Translational Molecular Medicine; The Netherlands), PCMM project (grant 03O-203). |
| Keywords: | Phosphodiesterase, prostate cancer, risk stratification, prognosis, molecular biomarkers, therapy resistance, castration resistance, DNA repair, neuroendocrine differentiation. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Gulliver, Chloe and Baillie, Professor George and Hoffmann, Dr Ralf |
| Authors: | Gulliver, C., Huss, S., Semjonow, A., Baillie, G. S., and Hoffmann, R. |
| College/School: | College of Medical Veterinary and Life SciencesCollege of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | British Journal of Cancer |
| Publisher: | Nature Publishing Group |
| ISSN: | 0007-0920 |
| ISSN (Online): | 1532-1827 |
| Published Online: | 22 September 2023 |
| Copyright Holders: | Copyright © The Author(s) 2023 |
| First Published: | First published in British Journal of Cancer 129(9):1462-1476 |
| Publisher Policy: | Reproduced under a Creative Commons license |
University Staff: Request a correction | Enlighten Editors: Update this record
Deposit and Record Details
| ID Code: | 305426 |
|---|---|
| Depositing User: | Ms Jacqui Brannan |
| Datestamp: | 06 Nov 2023 13:01 |
| Last Modified: | 19 Nov 2024 16:50 |
| Date of acceptance: | 24 August 2023 |
| Date of first online publication: | 22 September 2023 |
| Date Deposited: | 29 August 2023 |
| Data Availability Statement: | Yes |