# Exploring the feasibility of protein phosphatase 1–docking motif-mimetic cell-penetrating peptides for modulating prostate carcinogenesis

## TL;DR

This study explores using peptides that mimic docking motifs of protein phosphatase 1 to reduce prostate cancer cell viability, suggesting a new approach to targeting this enzyme in cancer treatment.

## Contribution

The novelty lies in demonstrating that cell-penetrating peptides mimicking PP1-docking motifs can reduce prostate cancer cell viability when used in combination.

## Key findings

- Peptides mimicking PP1-docking motifs were successfully internalized into prostate cancer cells.
- Combined treatment with all three peptides reduced cell viability by up to 80% in PC3 cells.
- No significant changes in androgen receptor or prostate-specific antigen expression were observed.

## Abstract

Once considered “undruggable,” protein phosphatases are now recognized as potential therapeutic targets. The serine and threonine–protein phosphatase 1 regulates key cellular processes and enhances androgen receptor activity in prostate cancer, even under castration-resistant conditions, suggesting a role in disease progression.

LNCaP and PC3 cells were treated with peptides mimicking protein phosphatase 1–docking motifs in androgen receptor, alongside known bioportides (MSS1 and mitoparan). Cellular uptake was assessed by confocal microscopy and fluorescence assays. Viability was measured with PrestoBlue, and androgen receptor and Prostate-Specific Antigen expression was analyzed by quantitative reverse transcription–polymerase chain reaction and Western blot.

Androgen receptor sequence contains 3 protein phosphatase 1–docking motifs: KVFF (binding site 1), HVVKW (binding site 2), and KPIYF (binding site 3). Binding site 1 and binding site 2 peptides were modified for better solubility, while binding site 3 was combined with the Tat sequence to enhance cellular uptake. Fluorophore-conjugated peptides successfully entered cells, with androgen receptor–binding site 3 showing the highest internalization in LNCaP cells (P = .0495). Treatment with the 3 androgen receptor–binding site peptides individually reduced cell viability in LNCaP and PC3 cells (P = .0352 and P = .0298, respectively). Combining androgen receptor–binding site peptides statistically reduced cell viability, particularly with all 3 peptides together (LNCaP: 68%, P = .0369; PC3: 80%, P = .0369). No statistically significant changes in androgen receptor or prostate-specific antigen expression were observed.

Bioportides targeting protein phosphatase 1–docking motifs, especially when combined, decrease prostate cancer cell viability, and additional protein phosphatase 1–interfering peptides such as MSS1 and mitoparan display potent cytotoxic effects. The absence of changes in androgen receptor and prostate-specific antigen expression highlights the need to further investigate their mechanisms of action.