| Project/Area Number |
20591622
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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 |
Digestive surgery
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| Research Institution | Chiba University |
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Principal Investigator |
TAKANO Shigetsugu Chiba University, 医学部附属病院, 助教 (20436380)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHITOMI Hideyuki 千葉大学, 医学部附属病院, 助教 (60375631)
FURUKAWA Katsunori 千葉大学, 医学部附属病院, 助教 (00400987)
KATO Atsushi 千葉大学, 大学院・医学研究院, 助教 (70344984)
SHIMIZU Hiroaki 千葉大学, 大学院・医学研究院, 講師 (80272318)
MIYAZAKI Masaru 千葉大学, 大学院・医学研究院, 教授 (70166156)
SHIDA Takashi 千葉大学, 医学部附属病院, 医員 (60456019)
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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 |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 膵臓外科学 / 膵臓癌 / 腫瘍マーカー / 抗癌剤耐性 / 個別化治療 |
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| Research Abstract |
Background : Although gemcitabine has been widely used as a first-line chemo reagent for patients with pancreatic cancer, the response rate still remains low. We previously identified Annexin II as a factor involved in gemcitabine resistance against pancreatic cancer. The aim of this study was to elucidate the signaling mechanism by which Annexin II induces gemcitabine resistance and to develop a new therapy which overcomes the resistance against gemcitabine.
Materials and methods : We comprehensively investigated and compared the specific profiles of 12 targeted phosphorylated signaling proteins in gemcitabine-resistant (GEM-MIA PaCa-2) and wild-type (WT-MIA PaCa-2) pancreatic cancer cell lines by the Bio-Plex phosphorylation protein assay system. We also evaluated the expression levels of Annexin II and two phosphoproteins, which showed different expression in these two cell lines, by immunohistochemistry of pancreatic cancer tissues.
Results : Annexin II overexpression in cancer cells was significantly associated with rapid recurrence after gemcitabine-adjuvant chemotherapy in patients with resected pancreatic cancer (P=0.0118). Bio-Plex analysis showed upregulation of p-Akt in GEM-MIA PaCa-2 cells in which Annexin II is highly expressed. On immunohistochemistry, the expression level of p-Akt was significantly correlated with that of p-mTOR in pancreatic cancer tissues. Inhibition of mTOR phosphorylation canceled gemcitabine resistance in GEM-MIA PaCa-2 cells.
Conclusion : The Akt/mTOR pathway is involved in the mechanisms of gemcitabine resistance induced by Annexin II in pancreatic cancer cells. Annexin II as an indicator for selection of gemcitabine resistance could thus be applied to the development of novel tailor-made approaches for pancreatic cancer treatment.
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