| Project/Area Number |
16390538
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathobiological dentistry/Dental radiology
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| Research Institution | Kochi University |
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Principal Investigator |
YAMAMOTO Tetsuya Kochi University, Dpt of Oral Surgery, Professor, 医学部, 教授 (00200824)
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| Co-Investigator(Kenkyū-buntansha) |
SASABE Eri Kochi University, Dpt of Oral Oncology, Research associate, 医学部附属病院, 助手 (40363288)
UETA Eisaku Kochi University, Dpt of Oral Oncology, Lecturer, 医学部附属病院, 講師 (10203431)
KAMATANI Takaaki Kochi University, Dpt of Oral Oncology, Research associate, 医学部附属病院, 助手 (00315003)
立石 善久 高知大学, 医学部, 助手 (20372732)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2005: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2004: ¥7,800,000 (Direct Cost: ¥7,800,000)
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| Keywords | hypoxia-inducible factor / apoptosis / squamous cell carcinoma cells / Akt / PI3-kinase / Bcl-2 family protein / radiation / chemotherapeutic drugs / Bco-2ファミリー蛋白質 |
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| Research Abstract |
The transcription factor hypoxia-inducible factor 1(HIF-1) plays an important role in solid tumor cell growth and survival. Over-expression of HIF-1α has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1α-induced survival pathways and the influence of HIF-1α on the susceptibility to chemotherapeutic drugs and γ-rays in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1α suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Over-expression of HIF-1α inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca^<2+> concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, anti-apoptotic Bcl-2 and Bcl-X_L levels were increased and pro-apoptotic Bax and Bak levels were decreas
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ed in the HIF-1α-overexpressing OSCC line. Over-expression of HIF-1α also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1α prevents apoptotic cell death through two mechanisms including inhibition of cytochrome c release and activation of Akt and ERK. Treatment with chemotherapeutic drugs and γ-rays enhanced the expression and nuclear translocation of HIF-1α and the susceptibility of OSCC cells to the drugs and γ-rays was negatively correlated with the expression level of HIF-1α protein. The over-expression of HIF-1α induced OSCC cells more resistant to the anticancer agents and the down-regulation of HIF-1α expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1α-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were down-regulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that down-regulation of HIF-1α expression is an effective strategy for cancer treatment. Less
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