Yu Miao, Wang Jinghe, Muller Daniel J, Helenius Jonne
1] Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland [2] Center for Precision Engineering, Harbin Institute of Technology, Harbin 150001, China.
Center for Precision Engineering, Harbin Institute of Technology, Harbin 150001, China.
Sci Rep. 2015 Feb 3;5:8206. doi: 10.1038/srep08206.
Eph receptor (Eph) and ephrin signaling can play central roles in prostate cancer and other cancer types. Exposed to ephrin-A1 PC3 prostate cancer cells alter adhesion to extracellular matrix (ECM) proteins. However, whether PC3 cells increase or reduce adhesion, and by which mechanisms they change adhesion to the ECM remains to be characterized. Here, we assay how ephrin-A1 stimulates PC3 cells to adhere to ECM proteins using single-cell force spectroscopy. We find that PC3 cells binding to immobilized ephrin-A1 but not to solubilized ephrin-A1 specifically strengthen adhesion to collagen I. This Eph-ephrin-A1 signaling, which we suppose is based on mechanotransduction, stimulates β1-subunit containing integrin adhesion via the protein kinase Akt and the guanine nucleotide-exchange factor cytohesin. Inhibiting the small GTPases, Rap1 or Rac1, generally lowered adhesion of PC3 prostate cancer cells. Our finding suggests a mechanism by which PC3 prostate cancer cells exposed to ephrins crosstalk to β1-integrins and preferably metastasize in bone, a collagen I rich tissue.
Eph受体（Eph）和ephrin信号传导在前列腺癌及其他癌症类型中可能发挥核心作用。暴露于ephrin-A1的PC3前列腺癌细胞会改变对细胞外基质（ECM）蛋白的黏附。然而，PC3细胞是增加还是减少黏附，以及它们通过何种机制改变对ECM的黏附仍有待确定。在此，我们使用单细胞力谱法测定ephrin-A1如何刺激PC3细胞黏附于ECM蛋白。我们发现，PC3细胞与固定化的ephrin-A1结合而非与可溶性ephrin-A1结合时，会特异性增强对I型胶原的黏附。我们推测这种基于机械转导的Eph-ephrin-A1信号传导通过蛋白激酶Akt和鸟嘌呤核苷酸交换因子细胞粘附素刺激含β1亚基的整合素黏附。抑制小GTP酶Rap1或Rac1通常会降低PC3前列腺癌细胞的黏附。我们的发现提示了一种机制，即暴露于ephrins的PC3前列腺癌细胞与β1整合素发生串扰，并更倾向于转移至富含I型胶原的骨组织中。
