2003 Fiscal Year Final Research Report Summary
Analysis of molecular mechanisms of chemoresistance in malignant glioma cells
| Project/Area Number |
14370438
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Cerebral neurosurgery
|
|---|
| Research Institution | Kumamoto University |
|---|
Principal Investigator |
SAYA Hideyuki Kumamoto University, Graduate School of Medical Sciences, Tumor Genetics & Biology, Professor, 大学院・医学薬学研究部, 教授 (80264282)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MIMORI Tatsuyuki Kumamoto University, Graduate School of Medical Sciences, Tumor Genetics & Biology, Associate Professor, 大学院・医学薬学研究部, 助教授 (00117384)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Keywords | brain tumor / checkpoint / mitotic catastrophe / chemoresistance / anti-tumor agents / mitosis / DNA damage / cancer |
|---|
| Research Abstract |
Cell cycle checkpoints prevent transition from one phase of the cell cycle to the next until all processes of the present phase are completed. Defects in the checkpoint functions result in gene mutations and chromosome damages, which contribute to the development and progression of tumors. However, loss of checkpoint function in some cancer cells is considered to be associated with their sensitivity to antineoplastic treatments such as chemotherapy and radiation. Most cancer cells including malignant gliomas are deficient in G_1 checkpoint function and therefore fail to arrest in G_1 phase on exposure to genotoxic agents. Instead, they accumulate temporarily in G_2 phase. However, given that the G_2 checkpoint is also partially impaired in cancer cells, they are unable to maintain G_2 arrest and eventually die as they enter mitosis. This process is known as mitotic catastrophe. The induction of mitotic catastrophe is an important goal of cancer therapies. In the present project, we characterized the dynamics of mitotic catastrophe induced by DNA damage in p53-deficient cancer cells. Most cells entering mitosis with DNA damage arrested at metaphase and subsequently underwent cell death. Furthermore, metaphase arrest prior to the catastrophe was clearly shown to result from activation of the spindle checkpoint, and inhibition of checkpoint function using RNA interference allowed cancer cells to escape mitotic catastrophe. Our findings suggest that the spindle checkpoint function is required for the induction of catastrophe in cancer cells treated with DNA-damaging antineoplastic agents. We speculate that chemoresistance of glioblastomas may be due to the impairment of spindle checkpoint function in those tumors.
|
-
-
-
-
-
-
-
-
-
-
[Publications] Iida S, Hirota T, Morisaki T, Marumoto T, Hara T, Kuninaka S, Honda S, Kosai K, Kawasuji, Pallas DC, Saya_H: "The tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G_1 tetraploidy checkpoint function."Oncogene. (in press). (2004)
Description
「研究成果報告書概要(欧文)」より
-
-
-
-
-
-
-
[Publications] Yunoue S, Tokuo H, Fukunaga K, Feng L, Ozawa T, Nishi T, Kikuchi A, Hattori S, Kuratsu J, Saya H, Araki N: "Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GAP function toward Ras."J Biol Chem. 278. 26958-26969 (2003)
Description
「研究成果報告書概要(欧文)」より
-
-
-
