Nur77 inhibits androgen-induced bladder cancer growth
Jianping Wu1, Jun Liu, Ruipeng Jia
1Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Abstract:
Currently, bladder cancer ranks as the second most common genitourinary malignancy which is exacting significant morbidity and mortality worldwide. Although there are abundant epidemiological and basic studies which strongly suggest the role of androgen hormone in bladder cancer, the underlying mechanism is not fully understood. In the current study, we sought to identify a new competitive inhibitor for androgen receptor in bladder cancer cells. Our results showed that Nur77 hyperexpression inhibits UM-UC-3 cell growth and cell cycle progression while Nur77 knockdown exerts the opposite effect. In our cell culture model, we also demonstrated that Nur77 competitively inhibits androgen-dependent transcription activity and more specifically, Nur77 competes with androgen receptor for binding to src-1, a well-known coactivator for steroids. More importantly, we also showed that a small molecule agonist for Nur77, Cytosporone B, significantly inhibits androgen-dependent bladder cancer cell growth in two different cell lines. These data provide a good proof-of-principle that Nur77 signaling machinery could be a new target for growth control of androgen-dependent bladder cancer cells.
Insights
Nur77 acts as a competitive inhibitor of the androgen receptor, suppressing bladder cancer cell growth. A Nur77 agonist, Cytosporone B, also shows potential for treating androgen-dependent bladder cancer.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Bladder cancer is a significant global health concern, with a suspected link to androgen hormones.
- The precise mechanisms by which androgens influence bladder cancer remain incompletely understood.
Purpose of the Study:
- To identify a novel competitive inhibitor for the androgen receptor (AR) within bladder cancer cells.
- To investigate the role of Nur77 in regulating androgen-dependent bladder cancer cell proliferation.
Main Methods:
- Utilized cell culture models (UM-UC-3 and other cell lines) to study Nur77 expression and its effects.
- Assessed androgen-dependent transcriptional activity and AR coactivator binding (src-1).
- Administered Cytosporone B, a small molecule Nur77 agonist, to evaluate its impact on cancer cell growth.
Main Results:
- Nur77 overexpression inhibited bladder cancer cell growth and cell cycle progression.
- Nur77 knockdown demonstrated opposite effects, promoting cell growth.
- Nur77 was shown to competitively inhibit AR-dependent transcription by binding to the coactivator src-1.
- Cytosporone B significantly inhibited androgen-dependent bladder cancer cell growth in multiple cell lines.
Conclusions:
- Nur77 functions as a competitive inhibitor of the androgen receptor in bladder cancer.
- Nur77 signaling presents a potential therapeutic target for managing androgen-dependent bladder cancer.
- Cytosporone B demonstrates therapeutic potential for bladder cancer treatment.
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