Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China; Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2395-2408. doi: 10.1016/j.bbadis.2018.04.019. Epub 2018 Apr 23.
An acidic extracellular pH (pHe) in the tumor microenvironment has been suggested to facilitate tumor growth and metastasis. However, the molecular mechanisms by which tumor cells sense acidic signal to induce a transition to an aggressive phenotype remain elusive. Here, we showed that an acidic pHe (pH 6.5) stimulation resulted in protrusion and epithelial-mesenchymal transition (EMT) of cancer cells, which promoted migration and matrix degeneration. Using computational molecular dynamics simulations, we reported acidic pHe-induced opening of the Integrin dimers (α5β1) headpiece which indicated the activation of integrin. Moreover, acidic pHe promoted maturation of focal adhesions, temporal activation of Rho GTPases and microfilament reorganization through integrin β1-activated FAK signaling. Furthermore, mechanical balance of cytoskeleton (actin, tubulin and vimentin) contributed to acidic pHe-triggered protrusion and morphology change. Taken together, these findings revealed that integrin β1 could be a novel pH-regulated sensitive molecule which confers protrusion and malignant phenotype of cancer cells.
酸性的细胞外 pH 值（pHe）被认为有助于肿瘤生长和转移。然而，肿瘤细胞感知酸性信号并诱导向侵袭表型转变的分子机制仍不清楚。在这里，我们表明酸性 pHe（pH 6.5）刺激导致癌细胞的突起和上皮-间充质转化（EMT），从而促进迁移和基质降解。使用计算分子动力学模拟，我们报告了酸性 pHe 诱导整合素二聚体（α5β1）头部的打开，这表明整合素的激活。此外，酸性 pHe 通过整合素 β1 激活的 FAK 信号促进了粘着斑的成熟、Rho GTPases 的短暂激活和微丝的重排。此外，细胞骨架（肌动蛋白、微管蛋白和波形蛋白）的力学平衡有助于酸性 pHe 触发的突起和形态变化。总之，这些发现表明整合素 β1 可能是一种新型的 pH 调节敏感分子，赋予癌细胞突起和恶性表型。
