Lee Hyung-Chahn, Park In-Chul, Park Myung-Jin, An Sungkwan, Woo Sang-Hyeok, Jin Hyeon-Ok, Chung Hee Yong, Lee Su-Jae, Gwak Ho-Shin, Hong Young-Jun, Yoo Doo-Hyun, Rhee Chang-Hun, Hong Seok-Il
Laboratory of Cell Biology, Department of Laboratory Medicine and Clinical Pathology, Korea Cancer Center Hospital, Seoul 139-240, Korea.
J Cell Biochem. 2005 Feb 15;94(3):597-610. doi: 10.1002/jcb.20312.
Non-steroidal anti-inflammatory drug (NSAID), sulindac has chemopreventive and anti-tumorigenic properties, however, the molecular mechanism of this inhibitory action has not been clearly defined. The Akt/protein kinase B, serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. In the present study, we demonstrate that down-regulation of Akt is a major effect of anti-invasiveness property of sulindac and its metabolites in glioblastoma cells. Myristoylated Akt (MyrAkt) transfected U87MG glioblastoma cells showed increase invasiveness, whereas DN-Akt transfected cells showed decrease invasiveness indicating that Akt potently promoted glioblastoma cell invasion. MMP-2 promoter and enzyme activity were up-regulated in Akt kinase activity dependent manner. Sulindac and its metabolites down-regulated Akt phosphorylation, inhibited MMP-2 production, and significantly inhibited invasiveness of human glioblastoma cells. In addition, sulindac and LY294002, a selective inhibitor of phosphoinositide 3-kinase (PI3K), synergistically inhibited the invasion of glioblastoma cells. Furthermore, only celecoxib showed Akt phosphorylation reduction and an anti-invasivness in glioblastoma cells, whereas aspirin, ketoprofen, ketorolac, and naproxen did not. In conclusion, our results provide evidence that down-regulation of Akt pathway and MMP-2 may be one of the mechanisms by which sulindac and its metabolites inhibit glioblastoma cell invasion.
非甾体抗炎药（NSAID）舒林酸具有化学预防和抗肿瘤特性，然而，这种抑制作用的分子机制尚未明确界定。Akt/蛋白激酶B，即丝氨酸/苏氨酸激酶，是许多细胞存活信号通路的重要介质，广为人知。在本研究中，我们证明Akt的下调是舒林酸及其代谢产物在胶质母细胞瘤细胞中抗侵袭特性的主要作用。肉豆蔻酰化Akt（MyrAkt）转染的U87MG胶质母细胞瘤细胞显示侵袭性增加，而显性负性Akt（DN-Akt）转染的细胞显示侵袭性降低，这表明Akt有力地促进了胶质母细胞瘤细胞的侵袭。基质金属蛋白酶-2（MMP-2）启动子和酶活性以Akt激酶活性依赖的方式上调。舒林酸及其代谢产物下调Akt磷酸化，抑制MMP-2产生，并显著抑制人胶质母细胞瘤细胞的侵袭。此外，舒林酸和磷酸肌醇3激酶（PI3K）的选择性抑制剂LY294002协同抑制胶质母细胞瘤细胞的侵袭。此外，只有塞来昔布显示在胶质母细胞瘤细胞中Akt磷酸化减少和抗侵袭性，而阿司匹林、酮洛芬、酮咯酸和萘普生则没有。总之，我们的结果提供了证据，表明Akt通路和MMP-2的下调可能是舒林酸及其代谢产物抑制胶质母细胞瘤细胞侵袭的机制之一。
