Molecular mechanism underlying HIF-1-mediated acquisition of anti-cancer drug resistance and investigation of efficient cancer chemotherapy

2015 Fiscal Year Final Research Report

• Project/Area Number: 26670164
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Nippon Medical School
• Principal Investigator: Tanaka Nobuyuki 日本医科大学, 医学(系)研究科(研究院), 教授 (80222115)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 肺癌 / HIF-1 / gefitinib / 耐性獲得 / 癌幹細胞

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.

Free Research Field

分子生物学