Inge Landon J, Rajasekaran Sigrid A, Wolle Daniel, Barwe Sonali P, Ryazantsev Sergey, Ewing Charles M, Isaacs William B, Rajasekaran Ayyappan K
Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, 1701 Rockland Road, Wilmington, DE 19803, USA.
Mol Cancer Ther. 2008 Jun;7(6):1386-97. doi: 10.1158/1535-7163.MCT-07-2029.
Loss of alpha-catenin is one of the characteristics of prostate cancer. The catenins (alpha and beta) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of beta-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where beta-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, beta-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of beta-catenin invariably are altered in cancer. Although a wealth of information is available about beta-catenin deregulation during oncogenesis, much less is known about how or whether alpha-catenin regulates beta-catenin functions. In this study, we show that alpha-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of beta-catenin. In alpha-catenin-null prostate cancer cells, reexpression of alpha-catenin increased cell-cell adhesion and decreased beta-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of beta-catenin is a major mechanism for decreased beta-catenin interaction with E-cadherin in alpha-catenin-null cells. alpha-Catenin attenuated the effect of Src phosphorylation by increasing beta-catenin association with E-cadherin. We also show that alpha-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that alpha-catenin is a key regulator of beta-catenin transcriptional activity and that the status of alpha-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.
α-连环蛋白的缺失是前列腺癌的特征之一。与E-钙黏蛋白相关的连环蛋白（α和β）在细胞间黏附的调节中起关键作用。β-连环蛋白的酪氨酸磷酸化使其与E-钙黏蛋白解离，并促进其进入细胞核，在细胞核中β-连环蛋白作为转录激活因子诱导参与细胞增殖的基因。因此，β-连环蛋白调节细胞间黏附和细胞增殖。控制β-连环蛋白这些功能之间平衡的机制在癌症中总是发生改变。尽管关于肿瘤发生过程中β-连环蛋白失调有大量信息，但对于α-连环蛋白如何或是否调节β-连环蛋白功能知之甚少。在本研究中，我们表明α-连环蛋白作为一个开关调节β-连环蛋白的细胞间黏附和增殖功能。在缺乏α-连环蛋白的前列腺癌细胞中，α-连环蛋白的重新表达增加了细胞间黏附，并降低了β-连环蛋白的转录活性、细胞周期蛋白D1水平和细胞增殖。此外，Src介导的β-连环蛋白酪氨酸磷酸化是缺乏α-连环蛋白的细胞中β-连环蛋白与E-钙黏蛋白相互作用减少的主要机制。α-连环蛋白通过增加β-连环蛋白与E-钙黏蛋白的结合来减弱Src磷酸化的作用。我们还表明α-连环蛋白增加了前列腺癌细胞对Src抑制剂抑制细胞增殖的敏感性。这项研究首次揭示α-连环蛋白是β-连环蛋白转录活性的关键调节因子，并且肿瘤组织中α-连环蛋白的表达状态可能对Src靶向治疗具有预后价值。
