Molecular mechanism underlying HIF-1-mediated acquisition of anti-cancer drug resistance and investigation of efficient cancer chemotherapy
| Project/Area Number |
26670164
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Nippon Medical School |
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Principal Investigator |
Tanaka Nobuyuki 日本医科大学, 医学(系)研究科(研究院), 教授 (80222115)
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 肺癌 / HIF-1 / gefitinib / 耐性獲得 / 癌幹細胞 / 非小細胞肺癌 / ゲフィチニブ耐性 / アポトーシス / Bim / Bcl-2ファミリー分子 / Erk / 薬剤耐性 / Gli1 / 炎症 |
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| Outline of Final Research Achievements |
In this research project, I analyzed the molecular mechanism underlying the acquisition of gefitinib, the EGFR specific tyrosine-kinase inhibitor, resistance in EGFR-positive non-small-cell lung cancer (NSCLC), and found that the expression of hypoxia-inducible factor (HIF)-1 is involved in gefitinib-resistance. In gefitinib-sensitive NSCLC cells, the expression of HIF-1alfa was suppressed by gefitinib treatment. In contrast, this suppression was not observed under HGF, which is known to induce gefitinib-resistance, stimulation and in gefitinib-resistant cells by mutation of tumor suppressor PREN. In addition, HIF-1 high expressing cells, the expression of anti-apoptotic Bcl-2 family proteins was enhanced. Moreover, I found that Erk signal-dependent stabilization of HIF-1alfa is involved in lung cancer stem cell maintenance. From these results, I showed that HIF-1 is important for acquisition of gefitinib-resistance and cancer stem cell maintenance in NSCLC cells.
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Report
(3 results)
Research Products
(15 results)
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[Journal Article] p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion.2014
Author(s)
Yamauchi S, Hou YY, Guo AK, Hirata H, Nakajima W, Yip AK, Yu CH, Harada I, Chiam KH, Sawada Y, Tanaka N, Kawauchi K.
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Journal Title
J Cell Biol.
Volume: 204
Issue: 7
Pages: 1191-207
DOI
Related Report
Peer Reviewed / Open Access
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