Identification of druggable targets from the interactome of the Androgen Receptor and Serum Response Factor pathways in prostate cancer.

Autor: Azam H; Cancer Biology and Therapeutics Laboratory, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland., Veale C; Cancer Biology and Therapeutics Laboratory, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland., Zitzmann K; Cancer Biology and Therapeutics Laboratory, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland., Marcone S; Department of Surgery, Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, Trinity College Dublin, Dublin, Ireland., Gallagher WM; Cancer Biology and Therapeutics Laboratory, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland., Prencipe M; Cancer Biology and Therapeutics Laboratory, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Dec 13; Vol. 19 (12), pp. e0309491. Date of Electronic Publication: 2024 Dec 13 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0309491
Abstrakt: Background: The Androgen Receptor (AR) pathway is crucial in driving the progression of prostate cancer (PCa) to an advanced state. Despite the introduction of second-generation AR antagonists, such as enzalutamide, majority of patients develop resistance. Several mechanisms of resistance have been identified, including the constitutive activation of the AR pathway, the emergence of AR spliced variants, and the influence of other signalling pathways. The Serum Response Factor (SRF) was previously identified as a possible player of resistance involved in a crosstalk with the AR signalling pathway. Elevated SRF levels in PCa patients were associated with disease progression and resistance to enzalutamide. However, the molecular mediators of the crosstalk between SRF and AR still need to be elucidated. The objective of this study was to identify common interactors of the AR/SRF crosstalk as therapeutic targets.
Methods: Here we used affinity purification mass spectrometry (MS) following immunoprecipitation of SRF and AR, to identify proteins that interact with both SRF and AR. The list of common interactors was expanded using STRING. Four common interactors were functionally validated using MTT assays.
Results: Seven common interactors were identified, including HSP70, HSP0AA1, HSP90AB1, HSAP5, PRDX1 and GAPDH. Pathway analysis revealed that the PI3k/AKT pathway was the most enriched in the AR/SRF network. Moreover, pharmacological inhibition of several proteins in this network, including HSP70, HSP90, PI3k and AKT, significantly decreased cellular viability of PCa cells.
Conclusions: This study identified a list of AR/SRF common interactors that represent a pipeline of druggable targets for the treatment of PCa.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Azam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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