| Project/Area Number |
14571892
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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 |
Surgical dentistry
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
MESE Hiroshi OKAYAMA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE AND DENTISTRY, ASSOCIATE PROFESSOR, 大学院・医歯学総合研究科, 助教授 (40325098)
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| Co-Investigator(Kenkyū-buntansha) |
SASAKI Akira OKAYAMA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE AND DENTISTRY, PROFESSOR, 大学院・医歯学総合研究科, 教授 (00170663)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | CDDP (Cisplatin) resistance / stress conditions in solid tumors / glucose-starved stress / Apoptosis / Glucose-regulated proteins (GRPs) / JNK1 / SAPK / Caspase-3 / Glicose-regulated proteins(GRPs) / CCDP(シスプラチン)耐性 |
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| Research Abstract |
Most solid tumor show resistance to current chemotherapy. This drug resistance can be associated with stress conditions, such as glucose starvation, low pH and hypoxia. These conditions are not observed in normal tissues. These tumor specific conditions commonly cause the glucose-regulated stress response of cancer cells.
We used CDDP resistant subline~ A431/CDDP2 from human epidermoid carcinoma cell line A431 as previously established. The glucose-starvated condition was up-regulate GRP78 and GRP94 in the parent A431 cell (A431/P). On the other hand, in A431/CDDP2, GRP78 and GRP94 levels were no change. The GRP78 and GRP94 inducing stress condition led to cellular sensitization to CDDP in A431/P cell only. DNA fragmentation of A431/P treated with 2-DG increased CDDP-induced apoptosis. A431/CDDP5 was not different with CDDP induced apoptosis in glucose starvated stress condition.
The reduction of CDDP induced apoptosis under glucose starvated stress condition was influenced by JNK1/SAPK and caspase-3 proteins. These results indicated that the reduction of CDDP-induced apoptosis can be considered as one of the CDDP resistant mechanisms in glucose-starvation condition.
In summery, our studies indicate that the effect of GRP78 and GRP94 not up-regulation and the reduction of CDDP-induced apoptosis is one of the CDDP resistant mechanisms in solid tumors. It will be useful to examine the effects of glucose-starvated condition on various apoptosis processes to further elucidate the molecular mechanism of the CDDP sensitization process. We believe such an examination will lead to a discovery of new strategy for enhancing the clinical effectiveness of CDDP by glucose-starvated stress condition such as up-regulating tumor GRP78 and GRP94.
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