2007 Fiscal Year Final Research Report Summary
Development of novel therapeutic method to regulate chemoresistance of leukemic cells acquired through aberrantly activated intracellular signaling mechanisms
| Project/Area Number |
18591046
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
Principal Investigator |
MIURA Osamu Tokyo Medical and Dental University, Department of Hematology, Professor (10209710)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Keywords | Chronic myeloid leukemia / BCR / ABL / Rap1 / B-Raf / Rottlerin / Imatinib / Arsenic trioxide / Ask1 |
|---|
| Research Abstract |
We aimed to elucidate the mechanisms involved in acquirement of chemoresistance by leukemic cells through aberrant activation of intracellular signaling events and to develop the method to overcome the chemoresistance. First, we revealed that rottlerin synergistically enhances imatinib-induced apoptosis of leukemic cells expressing the BCR/ABL fusion kinase, which activates various intracellular signaling pathways. We further found that the synergistic effect was mediated by mitochondrial uncoupling effect of rottlerin (Oncogene 26:2975-2987, 2007). Second, we found that the Mdm2 inhibitor nutlin-3a or the Bcl-2 family antagonist ABT-737 also synergistically enhance imatinib-induce apoptosis through synergistic activation of Bax and subsequent permeabilization of mitochondrial membrane and activation of caspases (manuscript in preparation). Third, we found that the expression level of cyclin D2 in hematopoietic cells including primary leukemic cells is regulated through phosphorylation of Thr280 by GSk3β or p38, which should play important roles in proliferation of leukemic cells induced by aberrant signal activation and in induction of cell cycle checkpoint by cellular stress (Oncogene 26:6630-40, 2007). Finally, we revealed that activation of Ask1 through ROS generation is involved in regulation of apoptosis in leukemic cells treated with arsenic trioxide (BBRC 355:1038-44, 2007).
|
