| Budget Amount *help |
¥3,850,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥150,000)
Fiscal Year 2007: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2006: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 2005: ¥2,800,000 (Direct Cost: ¥2,800,000)
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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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