Patel Maulik, Kawano Takeharu, Suzuki Nobuchika, Hamakubo Takao, Karginov Andrei V, Kozasa Tohru
Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.).
Mol Pharmacol. 2014 Sep;86(3):252-62. doi: 10.1124/mol.114.093914. Epub 2014 Jun 23.
Gastrin-releasing peptide receptor (GRPR) is ectopically expressed in over 60% of colon cancers. GRPR expression has been correlated with increased colon cancer cell migration. However, the signaling pathway by which GRPR activation leads to increased cancer cell migration is not well understood. We set out to molecularly dissect the GRPR signaling pathways that control colon cancer cell migration through regulation of small GTPase RhoA. Our results show that GRP stimulation activates RhoA predominantly through G13 heterotrimeric G-protein signaling. We also demonstrate that postsynaptic density 95/disk-large/ZO-1 (PDZ)-RhoGEF (PRG), a member of regulator of G-protein signaling (RGS)-homology domain (RH) containing guanine nucleotide exchange factors (RH-RhoGEFs), is the predominant activator of RhoA downstream of GRPR. We found that PRG is required for GRP-stimulated colon cancer cell migration, through activation of RhoA-Rho-associated kinase (ROCK) signaling axis. In addition, PRG-RhoA-ROCK pathway also contributes to cyclo-oxygenase isoform 2 (Cox-2) expression. Increased Cox-2 expression is correlated with increased production of prostaglandin-E2 (PGE2), and Cox-2-PGE2 signaling contributes to total GRPR-mediated cancer cell migration. Our analysis reveals that PRG is overexpressed in colon cancer cell lines. Overall, our results have uncovered a key mechanism for GRPR-regulated colon cancer cell migration through the Gα13-PRG-RhoA-ROCK pathway.
胃泌素释放肽受体（GRPR）在超过60%的结肠癌中异位表达。GRPR的表达与结肠癌细胞迁移增加相关。然而，GRPR激活导致癌细胞迁移增加的信号通路尚未完全明确。我们着手从分子层面剖析通过调控小GTP酶RhoA来控制结肠癌细胞迁移的GRPR信号通路。我们的结果表明，胃泌素释放肽（GRP）刺激主要通过G13异源三聚体G蛋白信号激活RhoA。我们还证明，含鸟嘌呤核苷酸交换因子（RH-RhoGEFs）的G蛋白信号调节因子（RGS）同源结构域（RH）成员——突触后密度95/盘状大蛋白/ZO-1（PDZ）-Rho鸟嘌呤核苷酸交换因子（PRG），是GRPR下游RhoA的主要激活剂。我们发现，PRG通过激活RhoA- Rho相关激酶（ROCK）信号轴，是GRP刺激的结肠癌细胞迁移所必需的。此外，PRG-RhoA-ROCK通路也有助于环氧化酶同工型2（Cox-2）的表达。Cox-2表达增加与前列腺素-E2（PGE2）产生增加相关，且Cox-2-PGE2信号促成了GRPR介导的癌细胞总迁移。我们的分析显示，PRG在结肠癌细胞系中过表达。总体而言，我们的结果揭示了GRPR通过Gα13-PRG-RhoA-ROCK通路调控结肠癌细胞迁移的关键机制。
