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

通过抗凋亡分子BCL-2/BAG-1抑制肿瘤转移

基本信息

批准号：
09670484
负责人：
ADACHI Masaaki
金额：
$ 2.05万
依托单位：
Sapporo Medical University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670484/
关键词：
Bcl-2 BAG-1 Metastasis anoikis Golgi apparatus Cell motility BAD 細胞運動能

项目摘要

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.

凋亡与细胞分化和发育密切相关。除了这些生理功能外，我们发现凋亡的抑制促进了癌症的转移和传播。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，尤其是转移和传播。在这个项目中，我们研究了Bcl-2/bag-1主要负面形式的过表达是否会导致肿瘤进展的降低。到目前为止，我们无法就此问题获得结论性结果。但是，我们还探索了有关BAG-1功能的几点，并证明BAG-1可以通过与细胞角蛋白和肌动蛋白丝的相互作用来促进细胞运动。我们还发现，BAG-1在正常上皮细胞中积聚在高尔基体。重要的是，BAG-1的细胞内定位在癌细胞中被破坏。 BAG-1在癌细胞中的异常分布可能与Bag-1的故障和改变细胞性质的功能有关，并有助于癌症的发展。此外，我们发现PKCα的激活会增加对厌氧菌的敏感性，因此激活可能对抑制转移有用，因为癌细胞在转移过程中无法附着细胞外基质。