| Co-Investigator(Kenkyū-buntansha) |
YOKOUCHI Masahiro Kagoshima University, orthopaedics, assistant, 大学院医歯学総合研究科, 助手 (80359976)
KOMIYA Setsurou Kagoshima University, orthopaedics, professor, 大学院医歯学総合研究科, 教授 (30178371)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
The protooncogene c-Cbl has emerged as an E3 ubiquity ligase for activated receptor tyrosine kinases and play a role as the negative regulator in the signal transduction. We reported that c-Cbl perform as the E3 ubiquitin ligase for the receptor tyrosine kinase, EGFR and non receptor yrosine kinase, Src (J.Biol.Chem : 1999, 2001). Now, we investigate the signal transduction mainly associated with c-Cbl and search for molecular targets for osteosarcoma. Recent reports showed that c-Src enables EGFR to evade degradation by promoting destruction of c-Cbl. This time, we analyze interaction of EGFR, Src and c-Cbl, and examine molecular targets for osteosarcoma. We demonstrate here that the complex of EGFR, Src and Cbl is formed by EGF stimulation and the signals transmit to the downstream in OS cell lines. And protein Src is thought to increase EGFR-induced signal transduction by promoting destruction of Cbl. Moreover, Src mRNA expression correlates lung metastasis, so might be the prognosis for osteosarcoma. In MTT essays, Src family tyrosine kinase nhibitor, PP1 inhibits the cell proliferation in the OS cell line, so Src might be a molecular target for osteosarcoma therapy.
Bisphosphonates (BPs) are currently most important class of inhibitors of osteoclast-mediated bone resorption and widely used in the treatment of osteoprosis and other osteocalst-mediated bone disease. Recently, it has been increased evidence that BPs also have direct anti-tumor activity on several cancer cell lines. However, the efficiency of BPs on osteosarcoma is not fully elucidated. Especially, there are no reports of the effects of the potent BP risedronate on human osteosarcoma cells. In this study we demonstrated that risedoronate is a potent inhibitor of osteosarcoma cells growth. Direct anti-tumor activity of risedronate on osteosarcoma cell lines implicated that risedronate could be an attractive agents for future therapy of osteosarcoma.
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