| Project/Area Number |
12213153
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | National Cancer Center |
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Principal Investigator |
ESUMI Hiroyasu National Cancer Center, Director, Research Institute East, 支所長 (70160364)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥43,900,000 (Direct Cost: ¥43,900,000)
Fiscal Year 2004: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 2003: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2001: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2000: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | AKT / AMPK / ARK5 / TGF-β / glucose-starvation / hypoxia / invasion / metastasis / 栄養飢餓耐性 / Akt / HNPCC / 大腸がん / 浸潤転移性 / ATM / MT1-MMP / 転移性 / 膵癌 / 腫瘍形成能 / AICAR / p53 / 膵臓がん / 栄養飢餓 / PKB / P13キナーゼ / 耐性 |
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| Research Abstract |
Cell lines derived from clinically hypovascular tumors, representatively pancreatic cancer and poorly differentiated adenocarcinomas of stomach and colon, were found to be extremely tolerant to glucose starvation. In addition, many cell lines were found to become tolerant to glucose starvation under hypoxic condition, that are otherwise sensitive under normoxic condition. These observations are unexpected because cells have been believed to require more glucose during hypoxia to generate energy by glycolysis under this condition. Biochemical mechanisms and molecules involved in the underlining mechanisms were investigated and two serine threonine protein kinases, AKT and AMPK were found to be in involved. In addition, a new AMPK-related protein kinase, ARK5 has been discovered and it was found to be activated by phosphorylation by AKT at its serine 600th. Interestingly ARK5 was found to be involved in not only in the tolerance to glucose starvation but also in the cell migration, invasion and metastasis both in vitro and in vivo using nude mice model. Analyses of mRNA expression among clinical colon cancers and multiple myelomas revealed ARK5 expression has an inverse correlation with poor patient outcome. Regarding to molecular mechanisms of hypoxia-induced tolerance to glucose starvation, TGF-f3 was found to be a key molecule. Among colon cancer cell lines, HCT-15, WiDr and DLD-1 showed clear hypoxia-induce tolerance but the induction was not observed in LoVo and HCT 116 which are derived from HNPCC patient and whose TGF-O receptor is inactivated. When expression vector of wild type TGF-I3 receptor was introduced into HCT-116 cells, the cells exhibited hypoxia-induced tolerance to glucose starvation. In addition, when TGF-13 was added to the medium of HepG2 cell or DLD-1, they became tolerant even under mormoxic condition. These observations clearly showed that TGF-p is a key molecule of the hypoxia-induced tolerance to glucose starvation.
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