Adrenergic Blockade Promotes Maintenance of Dormancy in Prostate Cancer Through Upregulation of GAS6.

Adrenergic Blockade Promotes Maintenance of Dormancy in Prostate Cancer Through Upregulation of GAS6. Transl Oncol. 2020 Apr 28;13(7):100781 Authors: Decker AM, Decker JT, Jung Y, Cackowski FC, Daignault-Newton S, Morgan TM, Shea LD, Taichman RS Abstract Men diagnosed with localized prostate cancer can develop metastases many years after initial treatment, resulting in a poor prognosis. The purpose of this study was to investigate the mechanisms by which signaling through norepinephrine (NE) may incite relapse of quiescent prostate cancer. We used an unbiased bioinformatics pipeline to examine mechanisms for recurrence related to sympathetic signaling in the bone marrow. A transcription factor cell array identified ATF1, RAR, and E2F as key nodes in prostate cancer cells exiting quiescence through adrenergic signaling. Subsequent secretome analysis identified GAS6 as affecting activity of these three factors, leading to cell cycle reentry. GAS6 expression was downregulated in osteoblasts through activation of the cAMP pathway and was targeted in vitro and in vivo using pharmacological agents (propranolol and phentolamine). Propranolol increased expression of GAS6 by osteoblasts, and phentolamine significantly inhibited expression. Propranolol treatment was sufficient to both increase GAS6 expression in marrow osteoblasts as well as eliminate the effects of NE signaling on GAS6 expression. These results demonstrate a strong correlatio...
Source: Translational Oncology - Category: Cancer & Oncology Authors: Tags: Transl Oncol Source Type: research