Nodularin-R Synergistically Enhances Abiraterone Against Castrate- Resistant Prostate Cancer via PPP1CA Inhibition

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Most prostate cancer (PCa) patients develop resistance to androgen deprivation therapy (ADT), including abiraterone, leading to castration-resistant prostate cancer (CRPC).
• Understanding abiraterone resistance mechanisms is crucial for developing effective treatments for advanced PCa.

Purpose of the Study:

• To identify genes conferring resistance to abiraterone in CRPC cells.
• To investigate the role of identified genes in abiraterone resistance and explore potential therapeutic interventions.

Main Methods:

• Genome-wide CRISPR/Cas9 screening in 22Rv1 CRPC cells to identify abiraterone-resistance genes.
• Bioinformatic analysis, gene silencing/overexpression, molecular docking, molecular dynamics simulations, cellular assays, and in vivo experiments.
• Validation of a natural product, nodularin-R, for its ability to target the identified resistance gene and enhance abiraterone efficacy.

Main Results:

• Five abiraterone resistance genes were identified, with high Protein Phosphatase 1 Catalytic Subunit Alpha (PPP1CA) expression correlating with the worst prognosis in CRPC patients.
• PPP1CA was highly expressed in abiraterone-resistant cells; silencing PPP1CA resensitized cells to abiraterone, promoting apoptosis and inhibiting colony formation.
• Nodularin-R inhibited PPP1CA by attenuating its interaction with USP11, potentially promoting PPP1CA degradation.
• Combination therapy of nodularin-R and abiraterone synergistically inhibited CRPC cell function and tumor growth in vivo, reducing PPP1CA expression.

Conclusions:

• PPP1CA is a critical driver of abiraterone resistance in CRPC.
• Nodularin-R enhances abiraterone's anti-cancer effects by targeting PPP1CA, presenting a promising combination therapy for CRPC.