Cancer Institute, Xuzhou Medical University, Xuzhou, China.
Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
Cancer Sci. 2020 Dec;111(12):4417-4428. doi: 10.1111/cas.14676. Epub 2020 Oct 27.
Prolonged hypersecretion of catecholamine induced by chronic stress may correlate with malignant progression of cancer. β2-adrenergic receptor (β2-AR) overexpressed in certain cancer cells may translate the signals from neuroendocrine system to malignant signals by interacting with oncoproteins, such as Her2. In the present study, we demonstrate that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR-199a-5p and SIRT1 and also confirm that catecholamine induction triggers the activities of γ-secretase, leading to shedding of Her2 extracellular domain (ECD) by ADAM10 and subsequent intramembranous cleavage of Her2 intracellular domain (ICD) by presenilin-dependent γ-secretase, nuclear translocation of Her2 ICD, and enhanced transcription of tumor metastasis-associated gene COX-2. Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, nuclear localization of Her2 was significantly correlated with overexpression of β2-AR in human breast cancer tissues, indicating that catecholamine-induced β2-AR activation plays decisive roles in tumor metastasis. Our data also reveal that an unknown mechanism by which the regulated intramembrane proteolysis (RIP) initiated by β2-AR-mediated signaling controls a novel Her2-mediated signaling transduction.
慢性应激引起的儿茶酚胺过度分泌可能与癌症的恶性进展有关。某些癌细胞中β2-肾上腺素能受体（β2-AR）的过度表达可能通过与癌蛋白（如 Her2）相互作用，将神经内分泌系统的信号转导为恶性信号。在本研究中，我们证明儿茶酚胺刺激通过调节 miR-199a-5p 和 SIRT1 的表达来激活 ADAM10 的表达和蛋白水解活性，并且还证实儿茶酚胺诱导触发 γ-分泌酶的活性，导致 Her2 细胞外结构域（ECD）通过 ADAM10 脱落，随后 Her2 细胞内结构域（ICD）通过早老素依赖性 γ-分泌酶进行跨膜切割，Her2 ICD 核转位，并增强肿瘤转移相关基因 COX-2 的转录。儿茶酚胺的慢性刺激强烈促进了体外癌细胞的侵袭活性和小鼠自发性肿瘤肺转移。此外，Her2 的核定位与人类乳腺癌组织中β2-AR 的过度表达显著相关，表明儿茶酚胺诱导的β2-AR 激活在肿瘤转移中起决定性作用。我们的数据还揭示了一种未知的机制，即β2-AR 介导的信号转导启动的调控跨膜蛋白水解（RIP）控制一种新的 Her2 介导的信号转导。
