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Published on: March 6, 2018
Abiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in
Ekrem Basaran1, Ceyhan Hacioglu2
1Department of Urology, Faculty of Medicine, Düzce University, Düzce, Turkey.
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.
Insights
Abiraterone acetate (AA) induces endoplasmic reticulum (ER) stress, downregulating the androgen receptor (AR) in prostate cancer (PCa) cells. Targeting the PERK pathway may improve AA treatment efficacy for AR-driven PCa.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Prostate cancer (PCa) is a significant cause of cancer-related death in men.
- Treatment resistance, particularly in advanced castration-resistant PCa (CRPC), presents a major clinical challenge.
- Abiraterone acetate (AA), a CYP17A1 inhibitor, is used to treat metastatic CRPC, but its full mechanism of action requires elucidation.
Purpose of the Study:
- To investigate the mechanism by which abiraterone acetate (AA) affects androgen receptor (AR) expression in prostate cancer (PCa) cells.
- To determine if AA-induced endoplasmic reticulum (ER) stress plays a role in modulating AR expression.
- To explore the potential of targeting the ER stress pathway to enhance AA efficacy.
Main Methods:
- Prostate cancer cell lines (LNCaP and 22Rv1) were treated with varying concentrations of AA.
- Cytotoxicity, proliferation, and apoptosis were assessed using CCK-8, BrdU, and caspase-3/7 assays.
- Expression of ER stress markers (PERK, ATF4, CHOP) and AR was analyzed via RT-qPCR, Western blot, and immunofluorescence.
- Pharmacological inhibitors and activators of the PERK pathway were used to validate its role.
Main Results:
- AA demonstrated dose- and time-dependent cytotoxicity and reduced proliferation in both cell lines.
- AA significantly induced apoptosis in LNCaP cells.
- AA upregulated ER stress markers (PERK, ATF4, CHOP) and concurrently downregulated AR expression.
- Modulation of the PERK pathway pharmacologically confirmed its involvement in AA's effects on AR and cell viability.
Conclusions:
- Abiraterone acetate (AA) induces endoplasmic reticulum (ER) stress, leading to the transcriptional downregulation of the androgen receptor (AR).
- This ER stress-mediated AR suppression contributes to reduced PCa cell viability and proliferation.
- Targeting the PERK pathway presents a potential strategy to enhance the efficacy of AA in AR-driven prostate cancer.
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