Exploring the feasibility of PP1-docking motif-mimetic cell-penetrating peptides for modulating prostate carcinogenesis
Menée in vitro sur des cellules de cancer de la prostate, cette étude examine l'intérêt thérapeutique de peptides imitant les motifs d'ancrage de la phosphatase PP1
Once considered “undruggable,” protein phosphatases are now recognised as potential therapeutic targets. The serine/threonine-protein phosphatase 1 (PP1) regulates key cellular processes and enhances androgen receptor (AR) activity in prostate cancer (PCa), even under castration-resistant conditions, suggesting a role in disease progression.: LNCaP and PC3 cells were treated with peptides mimicking PP1 docking motifs in AR, alongside known bioportides (MSS1 and mitoparan). Cellular uptake was assessed by confocal microscopy and fluorescence assays. Viability was measured with PrestoBlue™, and AR/PSA expression was analysed by qRT-PCR and Western blot.Androgen Receptor sequence contains three PP1 docking motifs: KVFF (Binding Site 1 (BS1), HVVKW (BS2), and KPIYF (BS3). BS1 and BS2 peptides were modified for better solubility, while BS3 was combined with the Tat sequence to enhance cellular uptake. Fluorophore-conjugated peptides successfully entered cells, with AR-BS3 showing the highest internalisation in LNCaP cells (p = .0495). Treatment with the three different AR-BS peptides individually reduced cell viability in LNCaP and PC3 cells (p = .0352 and p = .0298, respectively). Combining AR-BS peptides significantly reduced cell viability, particularly with all three peptides together (LNCaP: 68%, p = .0369; PC3: 80%, p = .0369). No significant changes in AR or PSA expression were observed.Bioportides targeting PP1 docking motifs, especially when combined, decrease PCa cell viability, and additional PP1-interfering peptides such as MSS1 and mitoparan display potent cytotoxic effects. The absence of changes in AR/PSA expression highlights the need to further investigate their mechanisms of action.
JNCI Cancer Spectrum , article en libre accès, 2025