2001 Fiscal Year Final Research Report Summary
STUDIES ON NOVEL MOLECULAR MECHANISM OF HYPERTHERMIA FOR CANCER THERAPY
| Project/Area Number |
12672122
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | TOKYO UNIVERSITY OF PHARAMCY AND LIFE SCIENCE, SCHOOL OF PHARMACY |
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Principal Investigator |
ITO AKIRA TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCE, DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, PROFESSOR, 薬学部, 教授 (70096684)
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| Project Period (FY) |
2000 – 2001
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| Keywords | HYPERTHERMIA / HEAT SHOCK / MATRIX METALLOFROTEINASE / 3'5'-CYCLIC AMP / INVASION AND METASTASIS / VASCULAR ENDOTHELIAL CELL / GROWTH FACTOR |
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| Research Abstract |
The effect of hyperthermia on the production of membrane type-1 matrix metalloproteinase (MT1-MMP) which closely correlated with tumor invasiveness was examined. Heat shock at 42℃ for 3h suppressed the gene expression and production of MT1-MMP in cultured human fibrosarcoma HT-1080 cells and human squamous carcinoma A431 cells, and thereby resulted in the inhibition of progelatinase A/proMMP-2 activation. The heat shock simultaneously increased the release of tissue inhibitor of metalloproteinases-2(TIMP-2) from cell surface of HT-1080 cells. In an effort to clarify the heat shock-mediated transduction pathways, an intracellular 3', 5'-cyclic AMP(cAMP) was found to be transiently augmented in the heat shocked HT-1080 cells. When HT-1080 cells were treated with cAMP elevating reagents, forskolin and dibutyryl cAMP, instead of heat shock, the production and gene expression of MT1-MMP, the release of TIMP-2, and the activation of proMMP-2 were also suppressed. Furthermore, in vitro tumor invasion assay in a Matrigel model indicated that the transiently increased cAMP by forskolin as well as heat shock interfered with the invasive activity of HT-1080 cells. Therefore, the transient increase in intracellular cAMP by heat shock is an essential event which interferes with the tumor invasion. In addition, the heat shock suppressed the production of vascular endothelial cell growth factor (VEGF) which closely participates in the promotion of angiogenesis in tumor tissues. Therefore, these results indicated that hyperthermia actually has a novel anti-invasive effect along with the known mechanism of inhibiting tumor growth.
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[Publications] Sato, T., Koike, L., Miyata, Y., Hirata, M., Mimaki, Y., Sashida, Y., Yano, M. andIto, A.: "Inhibition of activator protein- 1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinase- 1 production and suppression of production of matrix metalloproteinase 1 and 9 in human fibrosarcoma HT-1080 cells."Cancer Research. 62(4). 1025-1029 (2002)
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