Targeting TR4 nuclear receptor-mediated p21 downregulation to increase apoptosis for reverse of the Enzalutamide-resistance in prostate cancer
Background: Enzalutamide (enz), also known as MDV3100, is a crucial treatment for advanced Castration-Resistant Prostate Cancer (CRPC). However, many patients develop enz resistance, leading to disease progression and recurrence. Testicular Nuclear Receptor-4 (TR4) has been implicated in regulat...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MRE Press
2025-05-01
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| Series: | Journal of Men's Health |
| Subjects: | |
| Online Access: | https://oss.jomh.org/files/article/20250604-561/pdf/JOMH2024121601.pdf |
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| Summary: | Background: Enzalutamide (enz),
also known as MDV3100, is a crucial treatment for advanced Castration-Resistant
Prostate Cancer (CRPC). However, many patients develop enz resistance, leading to
disease progression and recurrence. Testicular Nuclear
Receptor-4 (TR4) has been implicated in regulating prostate cancer initiation,
progression, metastasis and radiosensitivity. p21, a suppressor of cell growth,
is crucial in caspase-activated apoptosis through both p53-dependent and
-independent pathways. This study aimed to explore how TR4 contributes to
enz-resistance in CRPC and the involvement of p21. Methods:
Enz-resistant cell lines were generated by culturing C4-2 cells with increasing
enz doses from 10 μM to 80 μM for 100 days.
3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
assay (MTS) and Immunohistochemistry (IHC)-morphology assay
confirmed the establishment of resistant cells. After TR4 knockdown and
overexpression, Reverse Transcription Polymerase Chain Reaction (RT-PCR) and
Western Blot (WB) were used to detect TR4 and p21 expression changes and flow
cytometry was employed to assess apoptosis. Results: C4-2 MDV-R cells
were spindle-shaped and had a lower apoptosis rate than parental C4-2 cells under
enz treatment. TR4 expression was elevated in C4-2 MDV-R cells.
Overexpressing TR4 decreased the apoptosis rate of C4-2 cells treated
with 25 μM enz, while knocking down TR4 increased it.
Simultaneously, TR4 negatively regulated p21 expression. Knocking down
TR4 in C4-2 MDV-R cells enhanced apoptosis during enz treatment.
Conclusions: TR4 could be a potential therapy target in combination with
enz as the promising treatment for CRPC. |
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| ISSN: | 1875-6867 1875-6859 |