Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

Liang Lin; Fan Yan; Dandan Zhao; Meng Lv; Xiaodong Liang; Hui Dai; Xiaodan Qin; Yan Zhang; Jie Hao; Xiuyuan Sun; Yanhui Yin; Xiaojun Huang; Jun Zhang; Jin Lu; Qing Ge

doi:10.18632/oncotarget.7151

Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

Oncotarget. 2016 Mar 1;7(9):9844-58. doi: 10.18632/oncotarget.7151.

Authors

Liang Lin¹, Fan Yan², Dandan Zhao³, Meng Lv⁴, Xiaodong Liang⁵, Hui Dai¹, Xiaodan Qin¹, Yan Zhang¹, Jie Hao¹, Xiuyuan Sun¹, Yanhui Yin¹, Xiaojun Huang⁴, Jun Zhang¹, Jin Lu⁴, Qing Ge¹

Affiliations

¹ Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
² Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
³ Jining No.1 People's Hospital, Jining, Shandong 272011, China.
⁴ Peking University Institute of Hematology, People's Hospital, Beijing 100044, China.
⁵ Hangzhou Cancer Hospital, Hang Zhou 310002, China.

Abstract

Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin's important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis.

Keywords: STAT3; adhesion; integrin; multiple myeloma; reelin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Adhesion / physiology*
Cell Adhesion Molecules, Neuronal / genetics
Cell Adhesion Molecules, Neuronal / metabolism*
Cell Line, Tumor
Cell Movement / physiology
Cell Survival / physiology
Disease-Free Survival
Drug Resistance, Neoplasm / physiology*
Enzyme Activation
Extracellular Matrix Proteins / genetics
Extracellular Matrix Proteins / metabolism*
Fibronectins / metabolism
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Humans
Integrin alpha5beta1 / metabolism*
Integrin beta1 / metabolism*
Multiple Myeloma / drug therapy
Multiple Myeloma / mortality
Multiple Myeloma / pathology*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins pp60(c-src) / metabolism
RNA Interference
RNA, Small Interfering / genetics
Reelin Protein
STAT3 Transcription Factor / metabolism*
Serine Endopeptidases / genetics
Serine Endopeptidases / metabolism*
Syk Kinase / metabolism

Substances

Cell Adhesion Molecules, Neuronal
Extracellular Matrix Proteins
Fibronectins
Integrin alpha5beta1
Integrin beta1
Nerve Tissue Proteins
RNA, Small Interfering
Reelin Protein
STAT3 Transcription Factor
STAT3 protein, human
Focal Adhesion Protein-Tyrosine Kinases
Proto-Oncogene Proteins pp60(c-src)
SYK protein, human
Syk Kinase
Proto-Oncogene Proteins c-akt
RELN protein, human
Serine Endopeptidases