Corticotropin-releasing hormone receptors mediate apoptosis via cytosolic calcium-dependent phospholipase A2 and migration in prostate cancer cell RM-1
Corticotropin-releasing hormone receptors mediate apoptosis via cytosolic calcium-dependent phospholipase A2 and migration in prostate cancer cell RM-1
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DOI：
10.1530/jme-13-0270
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Li, Shengnan
中科院分区：
文献类型：
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作者：
Jin, Lai;Li, Chuanhua;Li, Shengnan
外周促肾上腺皮质激素释放激素受体（CRHR）是G蛋白偶联受体，根据组织类型发挥不同的作用。以前，我们发现CRHR介导的小鼠前列腺癌细胞系（RM-1）凋亡的机制是Bcl-2：Bax比例的改变，并且发现CRH通过CRHR抑制乳腺癌细胞的转化生长因子β迁移。在本研究中，我们研究了胞浆钙依赖性磷脂酶A（2）（cPLA（2））桥接CRHR激活和Bcl-2：Bax比率以及CRHR激活对细胞迁移的影响。cPLA（2）的沉默减弱了CRHR 1激动剂、CRH诱导的细胞凋亡和Bcl-2：Bax比率的降低，而cPLA（2）的沉默加重了CRHR 2激动剂、Urocortin 2（Ucn 2）抑制的细胞凋亡和Bcl-2：Bax比率的增加。CRH主要通过上调白细胞介素1 β（IL 1 β）而以时间和浓度依赖性方式增加cPLA（2）表达。Ucn 2既不通过肿瘤坏死因子α也不通过IL 1 β降低cPLA（2）表达。CRH抑制cPLA（2）mRNA的衰减，Ucn 2仅抑制其产生。CRHR 1或CRHR 2在HEK 293细胞中的过表达分别相应地上调或下调CRH或Ucn 2刺激后cPLA（2）的表达。此外，CRH和Ucn 2均诱导RM-1细胞迁移。我们的观察不仅建立了CRHRs和细胞迁移之间的关系，而且据我们所知，还首次证明cPLA（2）参与CRHR 1诱导的凋亡和CRHR 2抑制的凋亡。
Peripheral corticotropin-releasing hormone receptors (CRHRs) are G protein-coupled receptors that play different roles depending on tissue types. Previously, we discovered the mechanism of CRHR-mediated apoptosis of mouse prostate cancer cell line (RM-1) to be a change of Bcl-2: Bax ratio, and CRH was found to inhibit transforming growth factor beta migration of breast cancer cells via CRHRs. In the present study, we investigated cytosolic calcium-dependent phospholipase A(2) (cPLA(2)) bridging CRHR activations and Bcl-2: Bax ratio and the effect of CRHR activation on cell migration. Silencing of cPLA(2) attenuated a CRHR1 agonist, CRH-induced apoptosis, and the decrease of the Bcl-2: Bax ratio, whereas silencing of cPLA(2) aggravated CRHR2 agonist, Urocortin 2 (Ucn2)-inhibited apoptosis, and the increase of the Bcl-2: Bax ratio. CRH in a time-and concentration-dependent manner increased cPLA(2) expression mainly through interleukin 1 beta (IL1 beta) upregulation. Ucn2 decreased cPLA(2) expression through neither tumor necrosis factor alpha nor IL1 beta. CRH-suppressed decay of cPLA(2) mRNA and Ucn2 merely suppressed its production. Overexpression of CRHR1 or CRHR2 in HEK293 cells correspondingly upregulated or down-regulated cPLA(2) expression after CRH or Ucn2 stimulation respectively. In addition, both CRH and Ucn2 induced migration of RM-1 cells. Our observation not only established a relationship between CRHRs and cell migration but also for the first time, to our knowledge, demonstrated that cPLA(2) participates in CRHR1-induced apoptosis and CRHR2-inhibited apoptosis.