| Project/Area Number |
13470336
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Urology
|
|---|
| Research Institution | Kyushu University |
|---|
Principal Investigator |
NAITO Seiji Kyushu University, Graduate School of Medical Sciences, Department of Urology, Professor and Chairman, 大学院・医学研究院, 教授 (40164107)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YOKOMIZO Akira Kyushu University hospital, Department of Urology, Stuff Doctor, 大学病院, 助手 (60346781)
OKUMURA Koji Kyushu University, Faculty of Medical Science, Department of Urology, Stuff Doctor, 大学院・医学研究院, 助手 (40325519)
KOGA Hirofumi Kyushu University, Faculty of Medical Science, Department of Urology, Associate Professor, 大学院・医学研究院, 助教授 (20271108)
TSUNODA Toshiyuki Kyushu University hospital, department of Urology, Research Associate, 大学病院, 医員
後藤 健 九州大学, 医学部・附属病院, 助手 (70325447)
|
|---|
| Project Period (FY) |
2001 – 2003
|
| Project Status |
Completed (Fiscal Year 2003)
|
| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥10,900,000 (Direct Cost: ¥10,900,000)
|
|---|
| Keywords | urogenital cancer / drug resistance / IP_3R1 / overcoming of resistance / cDNA Microarrays / anti-cancer drug / cisplatin / bladder cancer / 膀胱腫瘍 / 抗がん剤耐性 / MDR1 / MRP1 / MRP2 / MRP3 / アドリアマイシン |
|---|
| Research Abstract |
To investigate the molecules that regulate the acquisition of cis-diamminedichloroplatinum(II)(cisplatin)-resistance, we performed cDNA microarrays using two pairs of parental and its cisplatin-resistant bladder cancer cell lines. We found a markedly reduced expression of Inositol 1,4,5-trisphosphate(IP_3) receptor type1(IP_3R1), endoplasmic reticulum(ER) membrane protein, in cisplatin-resistant cells. We also observed the induction of ER stress by cisplatin, which was accompanied by the phosphorylation of α-subunit of eukaryotic translation initiation factor 2(eIF-2α) only in the parental cell lines but not in resistant cell lines. The suppression of IP_3R1 expression using small interfering RNA(siRNA) in parental cells prevented eIF-2α phosphorylation and apoptosis, and resulted in decreased sensitivity to cisplatin. Oppositely, overexpression of IPs_3R1 in resistant cells induced eIF-2α phosphorylation and apoptosis, and increased sensitivity to cisplatin. These results suggest that cisplatin-induced downregulation of IP_3R1 expression was closely associated with the sensitivity of cisplatin via ER stress in bladder cancer cells. Further analyses of IP_3R1 expression level in patients before or after cisplatin treatment are presently in progress to confirm these findings. IP_3R1 could be a good molecular marker to predict cisplatin sensitivity and be a therapeutical molecular target of cisplatin in future.
|
