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Mol Cancer Res. 2019 Aug 8. pii: molcanres.0605.2018. doi: 10.1158/1541-7786.MCR-18-0605. [Epub ahead of print]

The β2-adrenergic receptor is a molecular switch for neuroendocrine transdifferentiation of prostate cancer cells.

Author information

1
Institute for Cancer Research, Oslo University Hospital.
2
Urology/Institute of Cancer Research, Oslo University Hospital.
3
Department of Tumor Biology, Oslo University Hospital, Institute for Cancer Research.
4
Institute of Cancer Research/Department of Clinical Medicine, Oslo University Hospital/University of Oslo.
5
Institute of Cancer Research, Oslo University Hospital.
6
University of Oslo.
7
Institute of Biomedicine, University of Eastern Finland.
8
Department of Medical Biosciences, Umeå University.
9
Department of Pathology/Department of Clinical Medicine, Oslo University Hospital/University of Oslo.
10
Nuffield Department of Surgical Sciences, University of Oxford.
11
Department of Urology and Department of Clinical Sciences, Division of Urological Cancers, Lund University.
12
Institute of Cancer Research/Department of Clinical Medicine, Oslo University Hospital/University of Oslo k.a.tasken@medisin.uio.no.

Abstract

The incidence of treatment-related neuroendocrine (NE) prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen deprivation therapy (ADT) or anti-androgens, and by activation of the β2-adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during androgen deprivation therapy (ADT) and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and NE genes. ADRB2 overexpression induced an NE-like morphology in both AR positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and NE genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low-ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence. Implications: This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC.

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