Androgen activates β-catenin signaling in bladder cancer cells

Yi Li, Yichun Zheng, Koji Izumi, Hitoshi Ishiguro, Bo Ye, Faqian Li, Hiroshi Miyamoto

Research output: Contribution to journalArticle

Abstract

Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/β-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and β-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of β-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and β-catenin in bladder tumors (PZ0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous β-catenin expression (P=0.0276), nuclear β-catenin expression (P=0.0802), and co-expression of nuclear AR and β-catenin (P=0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on β-catenin in AR-positive and AR-negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of β-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of β-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of β-catenin when co-localized with AR. Finally, co-immunoprecipitation revealed androgeninduced associations of AR with β-catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate β-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of β-catenin signaling possibly via formation of AR/β-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach.

Original languageEnglish (US)
Pages (from-to)293-304
Number of pages12
JournalEndocrine-Related Cancer
Volume20
Issue number3
DOIs
StatePublished - Jun 2013
Externally publishedYes

Fingerprint

Catenins
Urinary Bladder Neoplasms
Androgens
Androgen Receptors
Metribolone
TCF Transcription Factors
Cystectomy
Testosterone Congeners
Androgen Receptor Antagonists
Cytoplasmic and Nuclear Receptors
Immunoprecipitation

Keywords

  • Androgen receptor
  • Antiandrogen
  • Bladder cancer
  • TCF/LEF
  • Wnt/β-catenin

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Li, Y., Zheng, Y., Izumi, K., Ishiguro, H., Ye, B., Li, F., & Miyamoto, H. (2013). Androgen activates β-catenin signaling in bladder cancer cells. Endocrine-Related Cancer, 20(3), 293-304. https://doi.org/10.1530/ERC-12-0328

Androgen activates β-catenin signaling in bladder cancer cells. / Li, Yi; Zheng, Yichun; Izumi, Koji; Ishiguro, Hitoshi; Ye, Bo; Li, Faqian; Miyamoto, Hiroshi.

In: Endocrine-Related Cancer, Vol. 20, No. 3, 06.2013, p. 293-304.

Research output: Contribution to journalArticle

Li, Y, Zheng, Y, Izumi, K, Ishiguro, H, Ye, B, Li, F & Miyamoto, H 2013, 'Androgen activates β-catenin signaling in bladder cancer cells', Endocrine-Related Cancer, vol. 20, no. 3, pp. 293-304. https://doi.org/10.1530/ERC-12-0328
Li Y, Zheng Y, Izumi K, Ishiguro H, Ye B, Li F et al. Androgen activates β-catenin signaling in bladder cancer cells. Endocrine-Related Cancer. 2013 Jun;20(3):293-304. https://doi.org/10.1530/ERC-12-0328
Li, Yi ; Zheng, Yichun ; Izumi, Koji ; Ishiguro, Hitoshi ; Ye, Bo ; Li, Faqian ; Miyamoto, Hiroshi. / Androgen activates β-catenin signaling in bladder cancer cells. In: Endocrine-Related Cancer. 2013 ; Vol. 20, No. 3. pp. 293-304.
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