Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells

Nianli Liu; Tianran Chen; Xiaohong Wang; Darong Yang; Binbin Xue; Haizhen Zhu

doi:10.1016/j.febslet.2015.02.026

Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells

FEBS Lett. 2015 Apr 2;589(8):897-903. doi: 10.1016/j.febslet.2015.02.026. Epub 2015 Mar 3.

Authors

Nianli Liu¹, Tianran Chen², Xiaohong Wang², Darong Yang², Binbin Xue², Haizhen Zhu³

Affiliations

¹ Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China; Research Center of Cancer Prevention & Treatment, Translational Medicine Research Center of Liver Cancer, Hunan Provincial Tumor Hospital (Affiliated Tumor Hospital of Xiangya Medical School of Central South University), Changsha 410013, China.
² Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China.
³ Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China; Research Center of Cancer Prevention & Treatment, Translational Medicine Research Center of Liver Cancer, Hunan Provincial Tumor Hospital (Affiliated Tumor Hospital of Xiangya Medical School of Central South University), Changsha 410013, China. Electronic address: zhuhaizhen69@yahoo.com.

PMID: 25747387
DOI: 10.1016/j.febslet.2015.02.026

Abstract

To investigate TRAIL resistance mechanisms in hepatocellular carcinoma (HCC), we isolated a stable TRAIL-resistant sub-population of the HCC cell line LH86, designated LH86-TR. Differential activation of AKT was not responsible for acquisition of TRAIL resistance. Cells with both congenital and acquired resistance to TRAIL exhibited increased Msi1 expression, which conferred TRAIL resistance by activating ERK. Forced expression of Msi1 decreased the sensitivity of HCC cells to TRAIL both in vitro and in vivo. Conversely, shRNA-mediated depletion of Msi1 enhanced TRAIL efficacy. SiRNA-mediated depletion of ERK overcame TRAIL resistance. Hence, we conclude that Msi1 is a mediator of TRAIL resistance in HCC cells.

Keywords: Drug resistance; ERK; Hepatocellular carcinoma; Msi1; Tumor necrosis factor-related apoptosis-inducing ligand.

Publication types

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

MeSH terms

Apoptosis / drug effects
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cell Survival / drug effects
Drug Resistance, Neoplasm*
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Humans
Liver Neoplasms / pathology*
MAP Kinase Signaling System / drug effects
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Protein Kinase Inhibitors / pharmacology
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
TNF-Related Apoptosis-Inducing Ligand / pharmacology*

Substances

Biomarkers, Tumor
MSI1 protein, human
Nerve Tissue Proteins
Protein Kinase Inhibitors
RNA-Binding Proteins
TNF-Related Apoptosis-Inducing Ligand
Extracellular Signal-Regulated MAP Kinases