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
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DOI：
10.1016/j.tranon.2020.100781
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发表时间：
2020-07-01
影响因子：
5
通讯作者：
Taichman, Russell S.
中科院分区：
文献类型：
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作者：
Decker, Ann M.;Decker, Joseph T.;Taichman, Russell S.
被诊断患有局限性前列腺癌的男性可能在初次治疗多年后出现转移，导致预后不良。本研究的目的是调查去甲肾上腺素 (NE) 信号传导可能引发静止期前列腺癌复发的机制。我们使用公正的生物信息学流程来检查与骨髓中交感神经信号传导相关的复发机制。转录因子细胞阵列将 ATF1、RAR 和 E2F 鉴定为前列腺癌细胞通过肾上腺素信号传导退出静止状态的关键节点。随后的分泌组分析确定 GAS6 影响这三个因子的活性，导致细胞周期重新进入。通过激活 cAMP 通路，成骨细胞中 GAS6 的表达下调，并在体外和体内使用药物（普萘洛尔和酚妥拉明）进行靶向。普萘洛尔增加成骨细胞 GAS6 的表达，酚妥拉明显着抑制表达。普萘洛尔治疗足以增加骨髓成骨细胞中的 GAS6 表达并消除 NE 信号传导对 GAS6 表达的影响。这些结果表明肾上腺素信号传导、GAS6 表达和前列腺癌复发之间存在很强的相关性，为高转移风险患者提供了新的治疗方向。
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 norepineph-rine (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 iden-ti fied ATF1, RAR, and E2F as key nodes in prostate cancer cells exiting quiescence through adrenergic signaling. Sub-sequent secretome analysis identi fied 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 signi ficantly inhibited expression. Propranolol treatment was suf ficient to both increase GAS6 expression in marrow osteoblasts as well as eliminate the effects of NE signaling on GAS6 expres-sion. These results demonstrate a strong correlation between adrenergic signaling, GAS6 expression, and recurrence in prostate cancer, suggesting a novel therapeutic direction for patients at high risk of metastasis.