Japanese Foundation for Cancer Research

About: Japanese Foundation for Cancer Research is a nonprofit organization based out in Tokyo, Japan. It is known for research contribution in the topics: Cancer & Breast cancer. The organization has 2676 authors who have published 5482 publications receiving 221859 citations.

The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium.

Abstract: Disruption of the DNA mismatch repair system, characterized by microsatellite instability (MI), plays an important role in the course of human carcinogenesis by increasing the rate of mutations of genes associated with cancers. However, it is not clear which genes are the target genes for mutation in the course of carcinogenesis. Microsatellites within the coding region of the transforming growth factor beta receptor type II (RII) and insulin-like growth factor II receptor (IGF-IIR) genes were reported to be targets for mutation during the course of carcinogenesis in MI+ tumors. Recently, somatic mutations were found in a poly(G)8 tract in the BCL-2-associated X protein (BAX) gene, one of the essential players in apoptosis, in some MI+ tumors. We examined mutations of BAX in MI+ cancers of various organs and found frameshift mutations at the poly(G)8 tract in 5 of 15 (33%) gastric cancers, 3 of 26 (12%) endometrial cancers, and 9 of 22 (41 %) colorectal cancers. In contrast, no such mutations were found in pancreatic cancer. These results suggest that mutations of BAX play an important role in the course of carcinogenesis in the stomach, colorectum, and endometrium.

Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

Abstract: Growth factors, cell-surface receptors, adhesion molecules, and extracellular matrix proteins play critical roles in vascular pathophysiology by affecting growth, migration, differentiation, and survival of vascular cells. In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using a retrovirus-mediated signal sequence trap method, we isolated a cell-surface protein named vasorin. Vasorin is a typical type I membrane protein, containing tandem arrays of a characteristic leucine-rich repeat motif, an epidermal growth factor-like motif, and a fibronectin type III-like motif at the extracellular domain. Expression analyses demonstrated that vasorin is predominantly expressed in vascular smooth muscle cells, and that its expression is developmentally regulated. To clarify biological functions of vasorin, we searched for its binding partners and found that vasorin directly binds to transforming growth factor (TGF)-β and attenuates TGF-β signaling in vitro. Vasorin expression was down-regulated during vessel repair after arterial injury, and reversal of vasorin down-regulation, by using adenovirus-mediated in vivo gene transfer, significantly diminished injury-induced vascular lesion formation, at least in part, by inhibiting TGF-β signaling in vivo. These results suggest that down-regulation of vasorin expression contributes to neointimal formation after vascular injury and that vasorin modulates cellular responses to pathological stimuli in the vessel wall. Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders.

Selective Activation of Apoptosis Program by S-p-bromobenzylglutathione Cyclopentyl Diester in Glyoxalase I-overexpressing Human Lung Cancer Cells

Abstract: Purpose : Glyoxalase I (GLO1) is an enzyme that plays a role in the detoxification of methylglyoxal, a side-product of glycolysis. We previously reported that GLO1 was a resistant factor to antitumor agent-induced apoptosis, and that S - p -bromobenzylglutathione cyclopentyl diester (BBGC), an effective inhibitor of GLO1, selectively sensitized to etoposide the drug-resistant human leukemia cells that overexpressed GLO1. In this study, we quantitatively measured GLO1 enzyme activity in various human solid tumor cells, and the antiproliferative effect of the GLO1 inhibitor was examined. Experimental Design: BBGC-induced apoptosis was assessed by flow cytometry. To evaluate antitumor activity of BBGC in vivo , we developed human cancer xenografts in nude mice. Results: We found that GLO1 enzyme activity was higher in all of the 38 human cancer cell lines that we examined than in the normal tissue samples. Moreover, GLO1 activity was frequently elevated in human lung carcinoma cells. Positive correlation between cellular GLO1 activity and BBGC sensitivity was observed in the lung cancer cell lines. Human lung cancer NCI-H522 and DMS114 cells, expressing higher GLO1 activity, underwent apoptosis when treated with BBGC, whereas A549 cells, expressing lower activity, did not. BBGC induced the activation of the stress-activated protein kinases c-Jun NH 2 -terminal kinase 1 (JNK1) and p38 mitogen-activated protein kinase (MAPK), which led to caspase activation in GLO1-overexpressing tumor cells. BBGC significantly inhibited the growth of xenografted DMS114 and human prostate cancer DU-145. Conclusions: Our present results indicate that GLO1 is a tumor-specific target enzyme especially in human lung carcinoma cells and that the GLO1 inhibitor is a potent chemotherapeutic agent to repress GLO1-overexpressing human tumors.