MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer.
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.
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Li
L
Sun
Lili
L
Liu
Xiangqiang
X
Liu
Yafang
Y
Wang
Mengbin
M
Li
Liping
L
Yao
Jianjun
J
Yang
Genlin
G
Ji
Changcun
C
Guo
Yanglin
Y
Pan
Shuhui
S
Liang
Biaoluo
B
Wang
Jie
J
Ding
Hongwei
H
Zhang
Yongquan
Y
Shi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D019008:Drug Resistance, Neoplasm; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017474:Receptors, Laminin / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D015854:Up-Regulation; D014750:Vincristine / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007797:Laminin; C470229:MGr1-antigen, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C510624:RPSA protein, human; D017474:Receptors, Laminin; D012269:Ribosomal Proteins; D014750:Vincristine; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases
CAM-DR; FAK/PI3K; MAPK; MGr1-Ag/37LRP; gastric cancer