β2-AR activation induces chemoresistance by modulating p53 acetylation through upregulating Sirt1 in cervical cancer cells.
β2-AR activation induces chemoresistance by modulating p53 acetylation through upregulating Sirt1 in cervical cancer cells.
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DOI：
10.1111/cas.13275
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发表时间：
2017-07
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：
Chen H;Zhang W;Cheng X;Guo L;Xie S;Ma Y;Guo N;Shi M
有人提出，儿茶酚胺诱导的 β2 肾上腺素受体 (β2-AR) 介导的信号传导可调节 p53 的降解。然而，潜在的分子机制尚不清楚。在本研究中，我们证明儿茶酚胺通过激活β2-AR介导的信号通路上调沉默信息调节因子1（Sirt1）的表达，因为选择性β2-AR拮抗剂ICI 118、551和非选择性β受体阻滞剂普萘洛尔有效抑制异丙肾上腺素（ISO）诱导的Sirt1表达。儿茶酚胺通过诱导 Sirt1 的表达来抑制阿霉素 (DOX) 诱导的 p53 乙酰化和转录激活活性。通过特异性 siRNA 敲低 Sirt1 表达，显着阻断了 ISO 对 DOX 诱导的 p53 乙酰化的抑制作用。此外，我们证明儿茶酚胺在体外和体内均可诱导宫颈癌细胞对化疗药物产生耐药性，并且 β2-AR 在宫颈癌组织中过度表达。我们的数据表明，儿茶酚胺通过激活 β2-AR 信号传导诱导 Sirt1 表达上调，可能会损害宫颈癌细胞中 p53 依赖性化疗诱导的细胞毒性。
It has been suggested that β2‐adrenergic receptor (β2‐AR)‐mediated signaling induced by catecholamines regulates the degradation of p53. However, the underlying molecular mechanisms were not known. In the present study, we demonstrated that catecholamines upregulated the expression of silent information regulator 1 (Sirt1) through activating β2‐AR‐mediated signaling pathway, since selective β2‐AR antagonist ICI 118, 551 and non‐selective β‐blocker proprenolol effectively repressed isoproterenol (ISO)‐induced Sirt1 expression. Catecholamines inhibited doxorubicin (DOX)‐induced p53 acetylation and transcription‐activation activities by inducing the expression of Sirt1. Knockdown of the Sirt1 expression by the specific siRNA remarkably blocked the inhibitory effects of ISO on DOX‐induced p53 acetylation. In addition, we demonstrated that catecholamines induced resistance of cervical cancer cells to chemotherapeutics both in vitro and in vivo and that β2‐AR was overexpressed in cervical cancer tissues. Our data suggest that the p53‐dependent, chemotherapeutics‐induced cytotoxicity in cervical cancer cells may be compromised by catecholamines‐induced upregulation of the Sirt1 expression through activating the β2‐AR signaling.