Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells

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• 作者：Shingo Kagawa ; MD ; PhD^a ; ^b ; Shigetsugu Takano ; MD ; PhD^a ; ^b ; Hideyuki Yoshitomi ; MD ; PhD^a ; ^{yoshitomi@faculty.chiba-u.jp} ; Fumio Kimura ; MD ; PhD^a ; Mamoru Satoh ; PhD^b ; Hiroaki Shimizu ; MD ; PhD^a ; Hiroyuki Yoshidome ; MD ; PhD^a ; Masayuki Ohtsuka ; MD ; PhD^a ; Atsushi Kato ; MD ; PhD^a ; Katsunori Furukawa ; MD ; PhD^a ; Kazuyuki Matsushita ; MD ; PhD^b ; Fumio Nomura ; MD ; PhD^b ; Masaru Miyazaki ; MD ; PhD^a
• 关键词：Annexin II ; Pancreatic cancer ; Gemcitabine ; Akt ; mTOR
• 刊名：Journal of Surgical Research
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：178
• 期：2
• 页码：758-767
• 全文大小：1279 K

文摘

Background

Although gemcitabine has been widely used as a first-line chemo reagent for patients with pancreatic cancer, the response rate remains low. We previously identified Annexin II as a factor involved in gemcitabine resistance against pancreatic cancer. The aims of this study were to elucidate the signaling mechanism by which Annexin II induces gemcitabine resistance and to develop a new therapy that overcomes the resistance against gemcitabine.

Methods

We compared the specific profiles of 12 targeted phosphorylated (p-) signaling proteins in gemcitabine-resistant (GEM-) and its wild-type pancreatic cancer cell lines (MIA PaCa-2) using the Bio-Plex assay system. We also evaluated the expression levels of Annexin II and two phosphoproteins, which showed different expressions in these two cell lines, by immunohistochemistry.

Results

Annexin II overexpression was significantly associated with rapid recurrence after gemcitabine-adjuvant chemotherapy in patients with resected pancreatic cancer (P?<?0.05). Bio-Plex analysis showed up-regulation of p-Akt in GEM-MIA PaCa-2 cells in which Annexin II is highly expressed. The expression level of p-Akt was significantly correlated with that of the downstream protein, p-mTOR, in pancreatic cancer tissues. Inhibition of mTOR phosphorylation canceled gemcitabine resistance in GEM-MIA PaCa-2 cells.

Conclusions

The Akt/mTOR pathway is involved in mechanisms of gemcitabine resistance induced by Annexin II in pancreatic cancer cells. This indicates that combination therapy with the mTOR inhibitor may overcome gemcitabine resistance. 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.