VTT Medical Biotechnology, Turku FIN-20520, Finland.
Mol Biol Cell. 2012 Sep;23(17):3357-69. doi: 10.1091/mbc.E12-03-0213. Epub 2012 Jul 18.
AKT1 and AKT2 kinases have been shown to play opposite roles in breast cancer migration and invasion. In this study, an RNA interference screen for integrin activity inhibitors identified AKT1 as an inhibitor of β1-integrin activity in prostate cancer. Validation experiments investigating all three AKT isoforms demonstrated that, unlike in breast cancer, both AKT1 and AKT2 function as negative regulators of cell migration and invasion in PC3 prostate cancer cells. Down-regulation of AKT1 and AKT2, but not AKT3, induced activation of cell surface β1-integrins and enhanced adhesion, migration, and invasion. Silencing of AKT1 and AKT2 also resulted in increased focal adhesion size. Importantly, the mechanisms involved in integrin activity regulation were distinct for the two AKT isoforms. Silencing of AKT1 relieved feedback suppression of the expression and activity of several receptor tyrosine kinases, including EGFR and MET, with established cross-talk with β1-integrins. Silencing of AKT2, on the other hand, induced up-regulation of the microRNA-200 (miR-200) family, and overexpression of miR-200 was sufficient to induce integrin activity and cell migration in PC3 cells. Taken together, these data define an inhibitory role for both AKT1 and AKT2 in prostate cancer migration and invasion and highlight the cell type-specific actions of AKT kinases in the regulation of cell motility.
AKT1 和 AKT2 激酶已被证明在乳腺癌迁移和侵袭中发挥相反的作用。在这项研究中，针对整合素活性抑制剂的 RNA 干扰筛选鉴定出 AKT1 是前列腺癌细胞中β1 整合素活性的抑制剂。验证实验研究了所有三种 AKT 同工型，结果表明，与乳腺癌不同，AKT1 和 AKT2 在 PC3 前列腺癌细胞中均作为细胞迁移和侵袭的负调节剂发挥作用。下调 AKT1 和 AKT2，但不是 AKT3，可诱导细胞表面β1 整合素的激活，并增强黏附、迁移和侵袭。沉默 AKT1 和 AKT2 还导致焦点黏附大小增加。重要的是，两种 AKT 同工型参与整合素活性调节的机制不同。沉默 AKT1 可缓解几种受体酪氨酸激酶（包括 EGFR 和 MET）的表达和活性的反馈抑制，这些激酶与β1 整合素有既定的交叉对话。另一方面，沉默 AKT2 会诱导 microRNA-200（miR-200）家族的上调，miR-200 的过表达足以诱导 PC3 细胞中的整合素活性和细胞迁移。总之，这些数据定义了 AKT1 和 AKT2 在前列腺癌细胞迁移和侵袭中的抑制作用，并强调了 AKT 激酶在调节细胞迁移中的细胞类型特异性作用。
