Ephexin4 and EphA2 mediate resistance to anoikis through RhoG and phosphatidylinositol 3-kinase
Ephexin4 and EphA2 mediate resistance to anoikis through RhoG and phosphatidylinositol 3-kinase
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DOI：
10.1016/j.yexcr.2011.05.014
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发表时间：
2011-07-15
影响因子：
3.7
通讯作者：
Katoh, Hironori
中科院分区：
文献类型：
--
作者：
Harada, Kohei;Hiramoto-Yamaki, Nao;Katoh, Hironori
细胞-细胞外基质相互作用的破坏导致上皮细胞经历称为失巢凋亡的凋亡，并且已经提出对失巢凋亡的抗性是癌细胞转移的关键步骤。EphA 2经常在多种人类癌症中过表达，并且最近的研究发现，EphA 2的过表达有助于恶性细胞行为，包括在几种不同类型的癌细胞中对失巢凋亡的抗性。在这里，我们表明，Ephexin 4，一个鸟嘌呤核苷酸交换因子的小GTdR的RhoG与EphA 2相互作用，在失巢凋亡的调节中起着重要的作用。Ephexin 4的敲低促进HeLa细胞中的失巢凋亡，并且使用敲低-拯救方法的实验显示RhoG、磷脂酰肌醇3-激酶（PI 3 K）和Akt的激活是Ephexin 4介导的失巢凋亡抑制所需的。事实上，Ephexin 4敲低导致悬浮培养的HeLa细胞中RhoG活性和Akt磷酸化的降低。此外，Ephexin 4参与EphA 2介导的失巢凋亡抑制。总之，这些结果表明，Ephexin 4通过激活EphA 2下游的RhoG和PI 3 K介导对失巢凋亡的抗性。(c)2011 Elsevier Inc. All rights reserved.
Disruption of cell-extracellular matrix interaction causes epithelial cells to undergo apoptosis called anoikis, and resistance to anoikis has been suggested to be a critical step for cancer cells to metastasize. EphA2 is frequently overexpressed in a variety of human cancers, and recent studies have found that overexpression of EphA2 contributes to malignant cellular behavior, including resistance to anoikis, in several different types of cancer cells. Here we show that Ephexin4, a guanine nucleotide exchange factor for the small GTPase RhoG that interacts with EphA2, plays an important role in the regulation of anoikis. Knockdown of Ephexin4 promoted anoikis in HeLa cells, and experiments using a knockdown-rescue approach showed that activation of RhoG, phosphatidylinositol 3-kinase (PI3K), and Akt was required for the Ephexin4-mediated suppression of anoikis. Indeed, Ephexin4 knockdown caused a decrease in RhoG activity and Akt phosphorylation in HeLa cells cultured in suspension. In addition, Ephexin4 was involved in the EphA2-mediated suppression of anoikis. Taken together, these results suggest that Ephexin4 mediates resistance to anoikis through activation of RhoG and PI3K downstream of EphA2. (c) 2011 Elsevier Inc. All rights reserved.