MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer

Authors

  • Li Sun,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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    • These authors contributed equally to this work.
  • Lili Liu,

    1. Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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    • These authors contributed equally to this work.
  • Xiangqiang Liu,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Yafang Wang,

    1. Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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  • Mengbin Li,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Liping Yao,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Jianjun Yang,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Genlin Ji,

    1. Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Changcun Guo,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Yanglin Pan,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Shuhui Liang,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Biaoluo Wang,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Jie Ding,

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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  • Hongwei Zhang,

    Corresponding author
    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
    • Yongquan Shi and Hongwei Zhang, State Key Laboratory of Cancer Biology, Institute of Digestive Diseases Xijing Hospital, Fourth Military Medical University, No. 15 Chang le West Road, Xi'an 710032, China.Tel: +86-29-82539041; Fax: +86-29-8477-1506;E-mails: shiyquan@fmmu.edu.cn; zhanghw@fmmu.edu.cn

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  • Yongquan Shi

    Corresponding author
    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
    • Yongquan Shi and Hongwei Zhang, State Key Laboratory of Cancer Biology, Institute of Digestive Diseases Xijing Hospital, Fourth Military Medical University, No. 15 Chang le West Road, Xi'an 710032, China.Tel: +86-29-82539041; Fax: +86-29-8477-1506;E-mails: shiyquan@fmmu.edu.cn; zhanghw@fmmu.edu.cn

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  • Funding information National Nature Science Foundation of China (81272349). 973 National Key Scientific Research Project (2010CB732400).

Abstract

It is well known that tumor microenvironment plays a vital role in drug resistance and cell adhesion-mediated drug resistance (CAM-DR), a form of de novo drug resistance. In our previous study, we reported that MGr1-Ag/37LRP ligation-induced adhesion participated in protecting gastric cancer cells from a number of apoptotic stimuli caused by chemotherapeutic drugs. Further study suggested that MGr1-Ag could prompt CAM-DR through interaction with laminin. However, the MGr1-Ag-initiated intracellular signal transduction pathway is still unknown. In this study, our experimental results showed that gastric cancer MDR cell lines mediated CAM-DR through upregulation of Bcl-2 by MGr1-Ag interaction with laminin. Further study found that, as a receptor of ECM components, MGr1-Ag/37LRP may activate the downstream signal pathway PI3K/AKT and MAPK/ERK through interaction with phosphorylated FAK. Moreover, the sensitivity to chemotherapeutic drugs could be significantly enhanced by inhibiting MGr1-Ag/37LRP expression through mAbs, siRNA, and antisense oligonucleotide. According to these results, we concluded that the FAK/PI3K and MAPK signal pathway plays an important role in MGr1-Ag-mediated CAM-DR in gastric cancer. MGr1-Ag/37LRP might be a potential effective reversal target to MDR in gastric cancer.

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