Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Center for Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan.
Cell Commun Signal. 2014 Nov 15;12:69. doi: 10.1186/s12964-014-0069-3.
Increased activity or expression of integrin-linked kinase (ILK), which regulates cell adhesion, migration, and proliferation, leads to oncogenesis. We identified the molecular basis for the regulation of ILK and its alternative role in conferring ERK1/2/NF-κB-mediated growth advantages to gastric cancer cells.
Inhibiting ILK with short hairpin RNA or T315, a putative ILK inhibitor, abolished NF-κB-mediated the growth in the human gastric cancer cells AGS, SNU-1, MKN45, and GES-1. ILK stimulated Ras activity to activate the c-Raf/MEK1/2/ERK1/2/ribosomal S6 kinase/inhibitor of κBα/NF-κB signaling by facilitating the formation of the IQ motif-containing GTPase-activating protein 1 (IQGAP1)-Ras complex. Forced enzymatic ILK expression promoted cell growth by facilitating ERK1/2/NF-κB signaling. PI3K activation or decreased PTEN expression prolonged ERK1/2 activation by protecting ILK from proteasome-mediated degradation. C-terminus of heat shock cognate 70 interacting protein, an HSP90-associated E3 ubiquitin ligase, mediated ILK ubiquitination to control PI3K- and HSP90-regulated ILK stabilization and signaling. In addition to cell growth, the identified pathway promoted cell migration and reduced the sensitivity of gastric cancer cells to the anticancer agents 5-fluorouracil and cisplatin. Additionally, exogenous administration of EGF as well as overexpression of EGFR triggered ILK- and IQGAP1-regulated ERK1/2/NF-κB activation, cell growth, and migration.
An increase in ILK non-canonically promotes ERK1/2/NF-κB activation and leads to the growth of gastric cancer cells.
整合素连接激酶（ILK）的活性或表达增加会导致肿瘤发生，因为它可以调节细胞黏附、迁移和增殖。我们确定了调节 ILK 的分子基础及其在赋予胃癌细胞 ERK1/2/NF-κB 介导的生长优势方面的替代作用。
用短发夹 RNA 或 T315（一种假定的 ILK 抑制剂）抑制 ILK，可消除 NF-κB 介导的人胃癌细胞 AGS、SNU-1、MKN45 和 GES-1 的生长。ILK 通过促进 IQ motif-containing GTPase-activating protein 1（IQGAP1）-Ras 复合物的形成来刺激 Ras 活性，从而激活 c-Raf/MEK1/2/ERK1/2/核糖体 S6 激酶/κB 抑制物α/NF-κB 信号通路。强制酶促 ILK 表达通过促进 ERK1/2/NF-κB 信号通路促进细胞生长。PI3K 激活或降低 PTEN 表达通过保护 ILK 免受蛋白酶体介导的降解来延长 ERK1/2 的激活。热休克同源物 70 相互作用蛋白的 C 端是 HSP90 相关的 E3 泛素连接酶，它介导 ILK 泛素化，以控制 PI3K 和 HSP90 调节的 ILK 稳定和信号转导。除了细胞生长外，鉴定出的途径还促进了细胞迁移，并降低了胃癌细胞对 5-氟尿嘧啶和顺铂等抗癌药物的敏感性。此外，外源性给予 EGF 以及过表达 EGFR 可触发 ILK 和 IQGAP1 调节的 ERK1/2/NF-κB 激活、细胞生长和迁移。
ILK 的增加非典型地促进 ERK1/2/NF-κB 的激活，导致胃癌细胞的生长。
