Sympathetic signaling facilitates progression of neuroendocrine prostate cancer

Shubham Dwivedi; Maricris Bautista; Sanskriti Shrestha; Hussain Elhasasna; Tanaya Chaphekar; Frederick S Vizeacoumar; Anand Krishnan

doi:10.1038/s41420-021-00752-1

Sympathetic signaling facilitates progression of neuroendocrine prostate cancer

Cell Death Discov. 2021 Nov 22;7(1):364. doi: 10.1038/s41420-021-00752-1.

Authors

Shubham Dwivedi^{1

2}, Maricris Bautista^{1

2}, Sanskriti Shrestha^{1

2}, Hussain Elhasasna³, Tanaya Chaphekar⁴, Frederick S Vizeacoumar³, Anand Krishnan^{5

6}

Affiliations

¹ Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
² Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK, S7K 0M7, Canada.
³ Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
⁴ Department of Arts and Science, University of Tennessee, Knoxville, TN, USA.
⁵ Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada. [email protected].
⁶ Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK, S7K 0M7, Canada. [email protected].

Abstract

The progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC.