GRK3 is a poor prognosticator and serves as a therapeutic target in advanced gastric adenocarcinoma.
GRK3 is a poor prognosticator and serves as a therapeutic target in advanced gastric adenocarcinoma.
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DOI：
10.1186/s13046-022-02463-6
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发表时间：
2022-08-23
期刊：
影响因子：
--
通讯作者：
Ajani JA
中科院分区：
文献类型：
--
作者：
Li Y;Fan Y;Xu J;Huo L;Scott AW;Jin J;Yang B;Shao S;Ma L;Wang Y;Yao X;Pool Pizzi M;Sewastjanow Da Silva M;Zhang G;Zhuo L;Cho EJ;Dalby KN;Shanbhag ND;Wang Z;Li W;Song S;Ajani JA
G蛋白偶联受体（GPCR）是美国食品药品监督管理局（FDA）批准的药物最常靶向的蛋白质家族。GPCR激酶3（GRK3）对GPCR信号传导至关重要。我们的基因组分析表明，GRK3的表达与胃腺癌（GAC）患者的不良预后相关。然而，GRK3在胃腺癌进展和转移中的功能及临床应用尚不清楚。
我们研究了GRK3在正常、原发性和转移性胃腺癌组织中的表达。我们通过化学文库筛选鉴定出一种新型的GRK3抑制剂LD2。通过对GRK3进行基因和药理学调控，在体外和体内进行了一系列功能和分子研究。确定了GRK3对YAP1及其靶标的影响。
与正常组织相比，GRK3在胃腺癌组织中过表达，在腹膜转移灶中表达更高。GRK3的过表达（OE）与较短的生存期显著相关。胃腺癌细胞中GRK3的上调增加了细胞侵袭、集落形成以及ALDH1⁺细胞的比例，而其下调则降低了这些特性。此外，LD2能强效且特异性地抑制GRK3，但不抑制与GRK3非常相似的GRK2。LD2在体外能高度抑制胃腺癌细胞的恶性表型。从机制上讲，GRK3上调胃腺癌组织中的YAP1及其转录下游靶点：SOX9、Birc5、Cyr61和CTGF。敲低（KD）YAP1可挽救胃腺癌细胞中GRK3过表达的表型。GRK3过表达显著促进肿瘤生长，但LD2在人源肿瘤异种移植（PDX）模型中抑制肿瘤生长，并显著抑制GRK3过表达诱导的腹膜转移。
GRK3是生存期的不良预后因素，赋予了侵袭性表型。GRK3的基因沉默或其抑制剂LD2可减弱GRK3所赋予的恶性特性，这表明GRK3是晚期胃腺癌的一个新的治疗靶点。
网络版包含补充材料，可在10.1186/s13046 - 022 - 02463 - 6获取。
G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3’s functions and clinical utility in GAC progression and metastases are unknown. We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined. GRK3 was overexpressed in GAC tissues compared to normal and was even higher in peritoneal metastases. Overexpression (OE) of GRK3 was significantly associated with shorter survival. Upregulation of GRK3 in GAC cells increased cell invasion, colony formation, and proportion of ALDH1+ cells, while its downregulation reduced these attributes. Further, LD2 potently and specifically inhibited GRK3, but not GRK2, a very similar kinase to GRK3. LD2 highly suppressed GAC cells’ malignant phenotypes in vitro. Mechanistically, GRK3 upregulated YAP1 in GAC tissues and its transcriptional downstream targets: SOX9, Birc5, Cyr61 and CTGF. Knockdown (KD) YAP1 rescued the phenotypes of GRK3 OE in GAC cells. GRK3 OE significantly increased tumor growth but LD2 inhibited tumor growth in the PDX model and dramatically suppressed peritoneal metastases induced by GRK3 OE. GRK3, a poor prognosticator for survival, conferred aggressive phenotype. Genetic silencing of GRK3 or its inhibitor LD2 blunted GRK3-conferred malignant attributes, suggesting GRK3 as a novel therapeutic target in advanced GAC. The online version contains supplementary material available at 10.1186/s13046-022-02463-6.
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DOI：
10.1158/1078-0432.ccr-14-2191
发表时间：
2015-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Song S;Honjo S;Jin J;Chang SS;Scott AW;Chen Q;Kalhor N;Correa AM;Hofstetter WL;Albarracin CT;Wu TT;Johnson RL;Hung MC;Ajani JA
通讯作者：
Ajani JA
影响因子：
3.5
作者：
BENOVIC, JL;STONE, WC;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ
影响因子：
24.5
作者：
Song, Shumei;Chen, Qiongrong;Ajani, Jaffer A.
通讯作者：
Ajani, Jaffer A.
DOI：
10.1016/j.jsps.2021.04.015
发表时间：
2021-06
期刊：
Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society
影响因子：
--
作者：
Alhosaini K;Azhar A;Alonazi A;Al-Zoghaibi F
通讯作者：
Al-Zoghaibi F
GRK3的高表达与胰腺导管腺癌的良好预后相关
影响因子：
2.8
作者：
Liu, Wen-Jing;Zhou, Li;Zhao, Yu-Pei
通讯作者：
Zhao, Yu-Pei