p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells
p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells
复制标题
DOI：
10.1007/s13277-010-0071-3
复制
发表时间：
2010-12-01
期刊：
影响因子：
--
通讯作者：
Jiang, Bo
中科院分区：
文献类型：
--
作者：
Wang, Xia;Gong, Wei;Jiang, Bo
p21活化激酶5 （PAK5）是最近发现的B组PAK家族成员。PAK蛋白是小GTPase Cdc42和Rac1的效应器，已知可调节细胞运动和激活细胞存活信号通路。特别是，PAK5的线粒体定位对其凋亡和细胞存活的影响至关重要。之前，我们证明了PAK5在结直肠癌（CRC）恶性进展过程中表达显著增加，PAK5通过调节CRC细胞粘附和迁移促进CRC转移。在本研究中，我们旨在探讨PAK5在喜树碱诱导的细胞凋亡中的作用及其可能的作用机制。我们的研究结果表明，PAK5的过表达通过抑制CRC细胞中caspase-8的活性来抑制喜树碱诱导的细胞凋亡。因此，在LoVo细胞中敲低PAK5导致细胞凋亡增加。在机制上，我们发现PAK5直接磷酸化Bad的丝氨酸112，并通过Akt途径间接导致丝氨酸136的磷酸化。总之，我们的研究揭示了PAK5在喜树碱诱导的细胞凋亡中的抑制作用，从而提示PAK5是CRC的一个新的治疗靶点。
p21-activated kinase 5 (PAK5) is a recently identified member of the group B PAK family. The PAK proteins are effectors of the small GTPase Cdc42 and Rac1 and are known to regulate cell motility and activate cell-survival signaling pathways. Especially, the mitochondrial localization of PAK5 is vital to its effects on apoptosis and cell survival. Previously, we demonstrated that PAK5 expression increased significantly during the malignant progression of colorectal carcinoma (CRC) and that PAK5 promoted CRC metastasis by regulating CRC cell adhesion and migration. In the present study, we aim to investigate the role of PAK5 in camptothecin-induced apoptosis and its potential mechanism of action. Our results showed that overexpression of PAK5 inhibited camptothecin-induced apoptosis by inhibiting the activity of caspase-8 in CRC cells. Accordingly, knockdown of PAK5 in LoVo cells resulted in increased apoptosis. Mechanistically, we found that PAK5 directly phosphorylated Bad on serine 112 and indirectly led to phosphorylation of serine 136 via the Akt pathway. In conclusion, our study revealed previously unappreciated inhibitory role of PAK5 in camptothecin-induced apoptosis, thus suggesting PAK5 as a novel therapeutic target in CRC.