2007 Fiscal Year Final Research Report Summary
Detection of novel biomarkers associated with carcinogenesis in pancreatic cancer using proteomic analysis
| Project/Area Number |
17500196
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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 |
Bioinformatics/Life informatics
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
SAITOU Hitoshi Tokyo Medical University, School of Medicine, Assistant Professor (80307321)
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| Co-Investigator(Kenkyū-buntansha) |
TUCHIDA Akihiko School of Medicine, 医学部, Associate Professor (50207396)
KASUYA Kazuhiko School of Medicine, 医学部, Instructor (80307313)
NAGAKAWA Yuichi School of Medicine, 医学部, Assistant Professor (20349484)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Pancreatic cancer / EGFR inhibitor / erlotinib / Focal adhesion kinase / SiRNA / molecular target therapy / Biomarker |
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| Research Abstract |
The epidermal growth factor receptor (EGFR) is a new molecular target therapy in most cancers. However, EGFR blockade alone may not completely control of growth of pancreas cancer. We found that FAK is overexpressed in EGFR inhibitor-resistant pancreatic cancer cell lines using proteomic analysis. This study investigated whether suppressing expression of FAK increase the anti-tumor effect of EGFR inhibitor. Furthermore, we examined the relation between Col I adhesion and anti-tumor effects of erlotinib. METHODS: Four human pancreatic cancer cell lines (AsPC, BxPC-3, HPAC, PANC-1) were used. To examined whether Col I adhesion has an influence on anti-tumor effects of erlotinib, we measured growth inhibition and apoptosis levels of each pancreatic cancer cells after erlotinib treatment in Col I coated flask or normal flask. Activation of EGFR-related signaling pathways such as Akt and MAPK after erlotinib treatment was determined by Western blotting Next, to determine whether FAK gene si
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lencing increase the anti-tumor effect of erlotinib in flask coated with Coll I. RESULTS: Growth inhibition and apoptosis in AsPC-1, BxPC-3, and HPAC cell lines after treatment of erlotinib was found in normal flask. However, growth inhibition and apoptosis level of AsPC-1 and BxPC-3 in Col I coated flask significantly decreased compare to them in normal flask. FAK expression was high in the AsPC-1, BxPC-3 and PANC1, and low in HPAC in normal fask. In AsPC-1, BxPC-3 and PANC, activation of FAK, Akt and ERK1/2 was observed after incubation in Coll I flask. FAK siRNA induced a marked decrease in activation of Akt and MAPK in AsPC-1, BxPC-3 and PANC. FAK siRNA induced growth inhibition in AsPC-1, BxPC-3 and PANC-1. Moreover, FAK siRNA treatment induced a large increase in growth inhibition and the apoptotic fraction of cells following erlotinib treatment in AsPC-1 and BxPC-3, which erlotinib anti-tumor effects were suppressed by Coll I adhesion. CONCLUSIONS: This study revealed that Col I adhesion suppress anti-tumor effects of erlotinib via FAK activation in pancreatic cancer. Furthermore, FAK sliceing increase the anti-tumor effect of EGFR inhibitor in pancreatic adenocarcinoma cells. These findings suggest that FAK might be a effective therapeutic target to improve cytotoxicity of EGFR inhibitor in pancreatic cancer. Less
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