| Project/Area Number |
20590077
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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 |
Biological pharmacy
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| Research Institution | Setsunan University |
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Principal Investigator |
ITO Fumiaki Setsunan University, 薬学部, 教授 (80111764)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIO Kazuto 近畿大学, 医学部, 教授 (10208134)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 上皮増殖因子受容体 / チロシンキナーゼ阻害剤 / ゲフィチニブ / 抗がん剤 / 抗がん剤耐性 / 非小細胞肺がん / アポトーシス / MKP-1 / Bim / ErbB3 |
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| Research Abstract |
Despite the dramatic efficacy of gefitinib and erlotinib in non-small cell lung cancer (NSCLC) patients with EGFR mutations, all patients ultimately develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). A secondary mutation in EGFR (T790M) and MET amplification have been identified as major mechanisms of acquired resistance to EGFR-TKIs. However, it is still important to identify additional mechanisms of resistance and to overcome acquired resistance to EGFR-TKIs in NSCLC patients. We previously reported that EGFR-TKI AG1478 induces apoptosis in PC-9 cells, a gefitinib-sensitive human NSCLC cell line with a mutation (delE746-A750) in tyrosine kinase domain of their EGFR. In this study, we repeatedly treated PC-9 cells with a high concentration of AG1478 (500 nM) and isolated AG1478-resistant cell lines. Expression level of ErbB3 in these resistant cells was extremely low as compared with that of PC-9 cells. Furthermore, PC-9 cells became resistant to AG1478, when their Erb
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B3 expression was down-regulated by siRNA. Therefore, the apoptosis-inducing action of AG1478 was correlated with the expression level of ErbB3. These results indicate that ErbB3 served to couple EGFR to the cell survival pathway in PC-9 cells and that the resistant cells could find a way to effectively activate survival signaling independent of.
We next treated PC-9 cells with a lower concentration of AG1478 (50 nM) and isolated another series of AG1478-resistant cell lines. In PC-9 cells, AG1478 decreased the expression of the MAPK phosphatase-1(MKP-1) and intensively stimulated phosphorylation of JNK. Further, AG1478 induced the accumulation of proapoptotic Bcl-2 family protein Bim in mitochondria. However, in the resistant cell lines, expression level of MKP-1 was still high after AG1478 treatment, and neither JNK phosphorylation nor accumulation of Bim was increased. These results indicate that translocation of Bim to mitochondria through the MKP-1/JNK pathway is critical for EGFR-TKI-induced apoptosis in PC-9 cells and that continuous high-level expression of MKP-1 leads to resistance to EGFR-TKIs. Less
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