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

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dc.contributor.authorBasaran, Ekrem
dc.contributor.authorHacioglu, Ceyhan
dc.date.accessioned2026-07-01T11:39:44Z
dc.date.available2026-07-01T11:39:44Z
dc.date.issued2026
dc.departmentDüzce Üniversitesi
dc.description.abstractObjectives: 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 mu M) 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 mu M) and 22Rv1 cells (24 h IC50 = 15.2 mu M) and proliferation decreased by 54.1% and 7.3% at 4.8 mu M, 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.
dc.identifier.doi10.1111/iju.70304
dc.identifier.issn0919-8172
dc.identifier.issn1442-2042
dc.identifier.issue1
dc.identifier.orcid0000-0001-8319-512X
dc.identifier.orcid0000-0002-0993-6118
dc.identifier.pmid41339287
dc.identifier.scopus2-s2.0-105023907815
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1111/iju.70304
dc.identifier.urihttps://hdl.handle.net/20.500.12684/23451
dc.identifier.volume33
dc.identifier.wosWOS:001630447400001
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley
dc.relation.ispartofInternational Journal of Urology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WOS_20260623
dc.subjectAbiraterone Acetate
dc.subjectAndrogen Receptor
dc.subjectEndoplasmic Reticulum (Er) Stress
dc.subjectProstate Cancer
dc.titleAbiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in Prostate Cancer
dc.typeArticle

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