Prostate cancer is the leading cancer diagnosed among men worldwide. The prostate cancer-associated mortality is due to the development of aggressive neuroendocrine prostate cancer (NEPC). Unfortunately, there is no effective treatment available for NEPC at present. This is due to the lack of proper understanding of the molecular switch that triggers neuroendocrine changes in prostate adenocarcinoma cells. Recent research demonstrated that peripheral nerves promote prostate cancer progression and metastasis. However, there is no clear understanding of the involvement of sympathetic nerves or their signaling in facilitating NEPC. In this work, we examined the effect of the sympathetic neurotransmitter norepinephrine (NE) in inducing neuroendocrine differentiation (NED) of prostate cancer cells in vitro. We used androgen-sensitive LNCaP and androgen-insensitive DU145 cells for the study. We examined the dose and time-dependent effect of NE in inducing NED-related phenotypic alterations in these cells using bright field and fluorescence imaging. NED-related molecular alterations were assessed using real-time PCR, western bot and immunocytochemistry. We found that NE induces characteristic NEPC morphological changes, such as compact cell bodies and neurite-like extensions, in both DU145 and LNCaP cells. At the mRNA level, NE induced the expression of the NED markers chromogranin B, synaptophysin and βIII tubulin in both cell types. Further immunoblot and immunostaining showed the upregulation of chromogranin B in these cells. We repeated the experiments in growth factor deprived conditions by avoiding fetal bovine serum in the cultures to mimic growth deprivation to prostate cancer cells, which they experience during androgen deprivation therapy. Surprisingly, the NE induced NED changes were more pronounced in the growth factor deprived conditions. Overall, our result indicates the potential of NE in inducing NED in prostate cancer cells and point towards a critical role for this sympathetic neurotransmitter in facilitating the development of NEPC.

Citation Format: Anand Krishnan, Shubham Dwivedi, Maricris Bautista, Tauqeer Iftikhar. Adrenergic signaling induces neuroendocrine differentiation of prostate adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB077.