The new approach of radiotherapy for the prevention of metastasis

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1. A Bcl-2-binding protein BAG-1 is identified as an anti-apoptotic molecule and binds to Raf-1, Hsp7O/Hsc7O, steroid hormone and hepatocyte growth factor (HGF) receptors, implicating multifunctions of BAG-1. In order to explore a method for suppression of cancer metastasis by irradiation, we establish an animal model which modulates metastasis potential of gastric cancer cells by overexpression of BAG-1 or Bcl-2. Namely, overexpression of BAG-1 in human gastric cancer cells led to prolonged cell survival against anoikis and increased peritoneal dissemination. In addition, we demonstrate that overexpression of BAG-1 strongly enhances the motility of human gastric cancer cells. In the gastric cancer MKN74 cells overexpression BAG-1, BAG1 colocalized with cytokeratin, and was concentrated at membrane ruffles induced by lysophosphatidic acid (LPA), resulting in partial colocalization with actin. These data strongly suggest cooperative roles of BAG-1 in the functions of epithelial cell cyt … More oskeletal proteins. Two independent migration assays showed that the BAG-1-expressing MKN74 cells exhibited strong enhancement of their migration compared with the control transfectants or parent MKN74 cells. In MKN74 cells, the overexpression of BAG-1 affected neither cell adhesion capability nor response to HGF.The promotive effect of BAG-1 on cell migration was similarly observed in transfectants of another human gastric cancer MKN45 cell line. Taken together, these studies demonstrate that BAG-1 is a good candidate as a target molecule for suppression of gastric cancer metastasis.2. We have also investigated several possible factors for determining apoptosis sensitivity to irradiation. By investigating JNK activity in more than 20 human cancer cell lines after irradiation, we found a tight correlation between an increase of JNK activity and sensitivity to irradiation-induced apoptosis.3. We have investigated the effect of irradiation on the surface antigen expression of proto-oncogene c-erb B-2 and intercellular adhesion molecule-1 (ICAM-l) on human adenocarcinoma cell lines. The expression ofthe Erb B-2 protein and ICAM-l on the cell membrane was found to increase by irradiation. The results suggest that the low dose radiation may be useful for accumulating LFA-1 positive cytotoxic T lymphocytes (CTL) at the local tumor tissue, which tumor cells may be attacked. Less