KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors
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Senyan Lai1,*, Guihua Wang1,*, Xiaonian Cao1, Xuelai Luo1, Guoping Wang2, Xianmin Xia3, Junbo Hu1, Jing Wang4
1Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
2Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
3Department of Bioengineering, Hubei University of Technology, Wuhan, 430068, China
4Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
*These authors have contributed equally to this work
Junbo Hu, e-mail: firstname.lastname@example.org
Jing Wang, e-mail: email@example.com
Keywords: p55PIK, Imatinib resistance, gastrointestinal stromal tumors
Received: June 13, 2015 Accepted: October 09, 2015 Published: October 22, 2015
Imatinib is the first-line drug for gastrointestinal stromal tumors (GISTs), as mutated KIT is closely associated with the occurrence of GIST. However, Imatinib resistance (IMA-resistance) occurs inevitably in most GIST patients. Although the over-expression of KIT in GIST is one of the major factors contributing to IMA-resistance, the underlying mechanism is still unclear. In this study, we demonstrate that p55PIK, an isoform of phosphoinositide 3-kinase (PI3K), increases KIT expression, leading to IMA-resistance in GISTs by activating NF-κB signaling pathway. Furthermore, down-regulation of p55PIK significantly decreases KIT expression and re-sensitizes IMA-resistance-GIST cells to Imatinib in vitro and in vivo. Interestingly, the expression of both p55PIK and KIT proteins is significantly increased in tumor samples from IMA-resistance-GIST patients, suggesting that p55PIK up-regulation may be important for IMA-resistance in the clinical setting. Altogether, our data provide evidence that p55PIK-PI3K signaling can contribute to IMA-resistance in GIST by increasing KIT expression. Moreover, p55PIK may be a novel potential drug target for treating tumors that develop IMA-resistance.
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