Inhibition of Hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression

Pramod S. Gowda, Jianhong D. Deng, Sweta Mishra, Abhik Bandyopadhyay, Sitai Liang, Shu Lin, Devalingam Mahalingam, Luzhe Sun

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Abstract

Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood. Here, we evaluated the hypothesis that combined inhibition of Hedgehog (Hh) and androgen receptor (AR) signaling will synergistically attenuate the growth of CRPC in vitro and in vivo. Androgen deprivation induced full-length androgen receptor protein levels in CRPC cells, but decreased its nuclear localization and transcriptional activity. However, androgen deprivation also increased a truncated form of androgen receptor (lacking ligand-binding domain) that possessed transcriptional activity in CRPC cells. Androgen deprivation also promoted the expression of Hh signaling components in CRPC cells, xenograft tumors, and the prostate glands of castrated mice. Importantly, although inhibition of either Hh or androgen receptor signaling alone was only moderately effective in blocking CRPC cell growth, combination of an Hh pathway inhibitor and a noncompetitive androgen receptor inhibitor synergistically suppressed the growth of CRPC cells in vitro and in vivo. Finally, noncompetitive inhibition of androgen receptor, but not competitive inhibition, was effective at limiting the activity of truncated androgen receptor leading to the inhibition of CRPC. Implications: Combined therapy using Hh inhibitors and a non-competitive AR inhibitor may limit CRPC growth.

Original languageEnglish (US)
Pages (from-to)1448-1461
Number of pages14
JournalMolecular Cancer Research
Volume11
Issue number11
DOIs
StatePublished - Nov 2013

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Hedgehogs
Castration
Androgen Receptors
Prostatic Neoplasms
Androgens
Growth
Neoplasms
Heterografts
Prostate
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Inhibition of Hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression. / Gowda, Pramod S.; Deng, Jianhong D.; Mishra, Sweta; Bandyopadhyay, Abhik; Liang, Sitai; Lin, Shu; Mahalingam, Devalingam; Sun, Luzhe.

In: Molecular Cancer Research, Vol. 11, No. 11, 11.2013, p. 1448-1461.

Research output: Contribution to journalArticle

Gowda, Pramod S. ; Deng, Jianhong D. ; Mishra, Sweta ; Bandyopadhyay, Abhik ; Liang, Sitai ; Lin, Shu ; Mahalingam, Devalingam ; Sun, Luzhe. / Inhibition of Hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression. In: Molecular Cancer Research. 2013 ; Vol. 11, No. 11. pp. 1448-1461.
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