Abiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in Prostate Cancer.

[OBJECTIVES] Prostate cancer (PCa) is a leading malignancy among men, with treatment resistance posing significant clinical challenges, especially in advanced, castration-resistant cases. Abiraterone acetate (AA), a CYP17A1 inhibitor, suppresses androgen biosynthesis and is used to manage metastatic disease; however, its complete mechanism of action is not fully understood. This study investigates whether AA modulates androgen receptor (AR) expression via endoplasmic reticulum (ER) stress in PCa.

[METHODS] LNCaP (androgen-sensitive) and 22Rv1 (AR-variant-expressing) PCa cells were treated with AA (0.5-16 μM) for 24-72 h. Cytotoxicity and proliferation were assessed via CCK-8 and BrdU assays. Apoptosis was quantified by caspase-3/7 activation. ER stress markers (PERK, ATF4, CHOP) and AR were evaluated using RT-qPCR, Western blot, and immunofluorescence staining. Pharmacological PERK inhibition (GSK2656157) and activation (CCT020312) validated pathway involvement.

[RESULTS] AA induced concentration/time-dependent cytotoxicity in LNCaP cells (24 h IC₅₀ = 4.8 μM) and 22Rv1 cells (24 h IC₅₀ = 15.2 μM) and proliferation decreased by 54.1% and 7.3% at 4.8 μM, respectively. AA triggered apoptosis in LNCaP cells, increasing caspase-3/7-positive cells to 71.58% vs. 1.73% in controls (p < 0.0001). Mechanistically, AA upregulated PERK, ATF4, and CHOP mRNA/protein (p < 0.0001) while downregulating AR. Immunofluorescence confirmed reciprocal ATF4 nuclear accumulation and AR reduction in AA-treated LNCaP cells. PERK inhibition reversed AA-induced effects, while PERK activation phenocopied AA's AR suppression and cytotoxicity, confirming ER stress mediation via the PERK/ATF4/CHOP axis.

[CONCLUSIONS] AA induces ER stress, leading to transcriptional downregulation of the AR and suppression of PCa cell viability and proliferation. Targeting the PERK pathway may enhance AA efficacy in AR-driven PCa.