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The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Peder R Braadland1,2, Håkon Ramberg1, Helene Hartvedt Grytli1

  • 1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Molecular Cancer Research : MCR
|August 10, 2019
PubMed

Insights

High beta-2 adrenergic receptor (ADRB2) expression is crucial for androgen-deprivation therapy-induced neuroendocrine prostate cancer development. ADRB2 downregulation precedes treatment-related neuroendocrine prostate cancer emergence, suggesting beta-blockers may prevent this transition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Treatment-related neuroendocrine prostate cancer (t-NEPC) incidence is increasing with advanced prostate cancer therapies.
  • Neuroendocrine transdifferentiation (NEtD) is a key step in t-NEPC development, potentially influenced by androgen deprivation and beta-2 adrenergic receptor (ADRB2) signaling.
  • Understanding the role of ADRB2 in NEtD could lead to strategies preventing or reversing t-NEPC.

Purpose of the Study:

  • To investigate the role of ADRB2 in androgen-deprivation therapy (ADT)-induced neuroendocrine transdifferentiation (NEtD) in prostate cancer.
  • To determine the correlation between ADRB2 expression and prostate cancer characteristics and treatment response.

Main Methods:

  • Analysis of ADRB2 mRNA and protein levels in treatment-naïve and treated prostate cancers.
  • In vitro studies using prostate cancer cell lines (LNCaP) to assess NEtD markers under androgen deprivation with varying ADRB2 levels.
  • Overexpression and downregulation of ADRB2 in prostate cancer cell lines.
  • In vivo xenograft studies in mice.

Main Results:

  • ADRB2 mRNA positively correlated with luminal markers and inversely with Gleason grade in primary prostate cancer.
  • ADRB2 mRNA was upregulated in metastatic disease but downregulated during ADT and t-NEPC emergence.
  • High ADRB2 expression was required for NEtD in LNCaP cells under androgen deprivation, evidenced by increased neurite outgrowth and neuroendocrine gene expression.
  • ADRB2 overexpression induced neuroendocrine morphology in AR-positive and AR-negative cells.
  • ADRB2 downregulation increased Wnt signaling, and GSK3α/β inhibition reduced neuroendocrine gene expression.
  • Castration-induced NEtD was more pronounced in xenografts from high ADRB2-expressing cells.

Conclusions:

  • High ADRB2 expression is essential for ADT-induced NEtD and subsequent t-NEPC emergence, with ADRB2 being downregulated during this process.
  • These findings suggest that beta-blockers could be a potential therapeutic strategy to prevent prostate cancer from evolving into t-NEPC.

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