β2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells.
β2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells.
复制标题
β2-AR的激活促进了HER2的切割和核转位，并促进了癌细胞的转移潜能。
DOI：
10.1111/cas.14676
复制
发表时间：
2020-12
期刊：
影响因子：
5.7
通讯作者：
Shi M
中科院分区：
文献类型：
--
作者：
Liu D;Zha L;Liu Y;Zhao X;Xu X;Liu S;Ma W;Zheng J;Shi M
慢性应激引起的儿茶酚胺长期高分泌可能与癌症的恶性进展有关。β2-肾上腺素能受体（β2-adrenergic receptor，β2-AR）在某些癌细胞中过表达，可能通过与癌蛋白（如Her 2）相互作用，将神经内分泌系统的信号转化为恶性信号。在本研究中，我们证明了儿茶酚胺刺激通过调节miR-199 a-5 p和SIRT 1的表达来激活ADAM 10的表达和蛋白水解活性，并且还证实了儿茶酚胺诱导触发了γ-分泌酶的活性，导致Her 2脱落细胞外结构域（ECD）被ADAM 10释放，随后由早老素依赖性γ-分泌酶膜内切割Her 2细胞内结构域（ICD），Her 2 ICD的核转位和肿瘤转移相关基因考克斯-2的转录增强。儿茶酚胺的慢性刺激强烈促进癌细胞的体外侵袭活动和小鼠自发性肿瘤肺转移。此外，Her 2的核定位与人乳腺癌组织中β2-AR的过表达显著相关，表明儿茶酚胺诱导的β2-AR活化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，通过这种机制，由β2-AR-介导的信号转导启动的受调节的膜内蛋白水解（RIP）控制着一种新的Her 2-介导的信号转导。在本研究中，我们证明了儿茶酚胺刺激通过调节miR-199 a-5 p和SIRT 1的表达来激活ADAM 10的表达和蛋白水解活性，并且还证实了儿茶酚胺诱导触发γ-分泌酶的活性，导致ADAM 10脱落Her 2 ECD，随后通过早老素依赖性γ-分泌酶膜内切割Her 2 ICD，Her 2 ICD的核转位，并增强肿瘤转移相关基因考克斯-2的转录。儿茶酚胺的慢性刺激强烈促进癌细胞的体外侵袭活动和小鼠自发性肿瘤肺转移。此外，Her 2的核定位与人乳腺癌组织中β2-肾上腺素能受体（β2-AR）的过表达显著相关，表明儿茶酚胺诱导的β2-AR活化在肿瘤转移中起决定性作用。
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. In the present study, we demonstrated 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 ECD by ADAM10 and subsequent intramembranous cleavage of Her2 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, the nuclear localization of Her2 was significantly correlated with overexpression of β2‐adrenergic receptor (β2‐AR) in human breast cancer tissues, indicating that catecholamine‐induced β2‐AR activation plays decisive roles in tumor metastasis.
登录
查看更多内容
影响因子：
17.1
作者：
Nilsson MB;Sun H;Diao L;Tong P;Liu D;Li L;Fan Y;Poteete A;Lim SO;Howells K;Haddad V;Gomez D;Tran H;Pena GA;Sequist LV;Yang JC;Wang J;Kim ES;Herbst R;Lee JJ;Hong WK;Wistuba I;Hung MC;Sood AK;Heymach JV
通讯作者：
Heymach JV
影响因子：
56.9
作者：
Luttrell, LM;Ferguson, SSG;Lefkowitz, RJ
通讯作者：
Lefkowitz, RJ
DOI：
10.1158/1078-0432.ccr-17-1864
发表时间：
2018-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chumsri S;Sperinde J;Liu H;Gligorov J;Spano JP;Antoine M;Moreno Aspitia A;Tan W;Winslow J;Petropoulos CJ;Chenna A;Bates M;Weidler JM;Huang W;Dueck A;Perez EA
通讯作者：
Perez EA
影响因子：
5.3
作者：
Giri, DK;Ali-Seyed, M;Hung, MC
通讯作者：
Hung, MC
DOI：
10.1083/jcb.200109033
发表时间：
2002-06-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Offterdinger M;Schöfer C;Weipoltshammer K;Grunt TW
通讯作者：
Grunt TW