Endothelin-1/endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis.
Endothelin-1/endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis.
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DOI：
10.1016/j.cellsig.2014.08.024
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发表时间：
2014-12
影响因子：
4.8
通讯作者：
Kim IM
中科院分区：
文献类型：
--
作者：
Teoh JP;Park KM;Wang Y;Hu Q;Kim S;Wu G;Huang S;Maihle N;Kim IM
内皮素-1（ET-1）/内皮素A受体（ETAR，一种G蛋白偶联受体）轴对肿瘤细胞和肿瘤微环境具有多效性作用，通过激活Gαq和β-抑制蛋白介导的途径调节化疗耐药性和其他肿瘤相关过程。虽然这些作用发生的确切机制仍有待阐明，但干扰ETAR信号转导已成为许多癌症（包括卵巢癌（OC））中有前途的抗肿瘤策略。然而，在缺乏下游信号传导的详细知识的情况下使用ETAR拮抗剂的当前临床方法导致多种不良副作用和有限的治疗功效。为了最大化ETAR靶向OC治疗的安全性和有效性，我们研究了其他G蛋白亚基如Gαs在ETAR介导的卵巢致癌信号传导中的作用。在HEY（人转移性OC）细胞中，ET-1/ETAR轴已得到充分表征，Gαs信号抑制ETAR介导的OC细胞迁移、伤口愈合、增殖和软琼脂上的集落形成，同时诱导OC细胞凋亡。从机制上讲，ET-1/ETAR在同一卵巢癌细胞系中与Gαs/cAMP信号传导偶联。Gαs/cAMP/PKA激活抑制血管生成/转移性Calcrl和Icam 2表达的ETAR介导的β-抑制蛋白激活。与我们的研究结果一致，在癌症基因组图谱数据分析中，Gαs过表达与OC患者生存率的改善相关。总之，我们的研究结果表明Gαs信号在ET-1/ETAR介导的OC肿瘤发生中具有新的功能，并可能为偏向性信号机制提供理论基础，该机制选择性激活Gα s偶联的肿瘤抑制通路，同时阻断Gαq-/β-arrestin介导的致癌通路，以改善OC中ETAR轴的靶向作用。
The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8.8
作者：
Archetti M
通讯作者：
Archetti M
影响因子：
5.8
作者：
Grant, ES;Brown, T;Habib, FK
通讯作者：
Habib, FK
影响因子：
9.7
作者：
Follin-Arbelet, Virginie;Torgersen, Maria Lyngaas;Blomhoff, Heidi Kiil
通讯作者：
Blomhoff, Heidi Kiil
影响因子：
11.5
作者：
Frey, UH;Alakus, H;Schmid, KW
通讯作者：
Schmid, KW