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Updated: Feb 19, 2026
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Targeting Hsp27/eIF4E interaction with phenazine compound: a promising alternative for castration-resistant prostate
Hajer Ziouziou1,2,3,4,5, Claudia Andrieu1,2,3,4, Erik Laurini6,7
1Inserm, UMR1068, CRCM, Marseille, France.
Abstract:
The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo.
Insights
Researchers identified a new way to treat advanced prostate cancer by disrupting the Hsp27/eIF4E interaction, a key factor in castration-resistant prostate cancer, leading to increased cell death.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Advanced prostate cancer treatment strategies often target genes activated by androgen withdrawal.
- Inhibiting survival proteins can cause cytotoxic effects, necessitating alternative therapeutic approaches.
- Disrupting specific protein-protein interactions offers a promising strategy to overcome treatment resistance.
Purpose of the Study:
- To identify the interaction site between heat shock protein 27 (Hsp27) and eukaryotic initiation factor 4E (eIF4E).
- To investigate the role of the Hsp27/eIF4E interaction in castration-resistant prostate cancer progression.
- To discover compounds that can inhibit this interaction and overcome treatment resistance.
Main Methods:
- Utilized a combination of experimental techniques and molecular modeling to map the Hsp27/eIF4E interaction site.
- Employed Bioluminescence Resonance Energy Transfer (BRET) assays and molecular simulations to screen for potential inhibitors.
- Evaluated the efficacy of identified compounds in vitro and in vivo models of prostate cancer.
Main Results:
- Confirmed that eIF4E interacts with the C-terminal region of phosphorylated Hsp27.
- Demonstrated that disrupting the Hsp27/eIF4E interaction enhances sensitivity to chemotherapy and hormone therapy.
- Identified phenazine derivative 14 as a potent inhibitor of the Hsp27/eIF4E interaction, reducing cell viability and increasing cell death.
Conclusions:
- The Hsp27/eIF4E interaction is a critical mechanism in castration-resistant prostate cancer.
- Inhibiting this interaction represents a novel therapeutic strategy for advanced prostate cancer.
- Phenazine derivative 14 shows potential as a therapeutic agent for treating chemo- and castration-resistant prostate cancer.
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