Suppression of tumor metastasis through anti-apoptotic molecules BCL-2/BAG-1

细胞凋亡与细胞分化和发育密切相关。除了这些生理功能外，我们还发现抑制细胞凋亡促进了肿瘤的转移和扩散。在这方面，抗凋亡分子被认为是致癌蛋白，我们的数据强烈表明，抑制抗凋亡分子可能会抑制肿瘤的进展，特别是转移和扩散。在本项目中，我们研究了显性阴性形式的Bcl-2/Bag-1的过度表达是否会导致肿瘤进展的减缓。到目前为止，我们还无法在这个问题上取得决定性的结果。然而，我们也探索了关于BAG-1功能的几个要点，并证明了BAG-1可以通过与细胞角蛋白和肌动蛋白细丝相互作用来促进细胞运动。我们还发现，BAG-1在正常上皮细胞的高尔基体中积聚。重要的是，BAG-1在癌细胞中的细胞内定位被打乱。BAG-1在肿瘤细胞中的异常分布可能与BAG-1功能障碍有关，改变了细胞的性质，促进了肿瘤的发展。此外，我们发现，由于癌细胞在转移过程中不能附着细胞外基质，PKCα的激活增加了对失巢凋亡的敏感性，因此这种激活可能有助于抑制转移。

Apoptosis is tightly linked to cellular differentiation and development. In addition to these physiological functions, we found that suppression of apoptosis promotes cancer metastasis and dissemination. In this regard, anti-apoptotic molecules are considered to be oncogenic proteins, and our data strongly suggest that suppression of anti-apoptotic molecules may inhibit tumor progression, especially metastasis and dissemination. In this project, we have investigated whether overexpression of dominant negative form of Bcl-2/BAG-1 can lead to decrease of tumor progression. So far, we could not obtain conclusive results on this issue. However, we also explored several points regarding BAG-1 functions and demonstrated that BAG-1 can contribute to cell motility through interaction with cytokeratin and actin filaments. We also found that BAG-1 accumulates at the Golgi apparatus in normal epithelial cells. Importantly, the intracellular localization of BAG-1 is disrupted in carcinoma cells. The aberrant distribution of BAG-1 in carcinoma cells may be associated with malfunction of BAG-1 and alter cellular properties and contribute to cancer development. In addition, we found that activation of PKC alpha increases sensitivity to anoikis, and thus the activation may be useful for inhibition of metastasis, since cancer cells can not attach extracellular matrix during metastasis.