title: A proteomic approach to elucidate the multiple targets of selenium-induced cell-growth inhibition in human lung cancer.
abstract: BACKGROUND
  Methylseleninic acid (MSA) has been implicated as a promising anticancer agent for lung cancer. However, the underlying molecular mechanism(s) responsible for MSA's action is not well understood. Our study aimed to examine the cellular effects of MSA on L9981 human high-metastatic large cell lung cancer cells and gain insights into its possible molecular mechanism(s) through a proteomic approach.
  
  
  METHODS
  L9981 cells were exposed to MSA at different concentrations and time points. The effects of MSA on cell proliferation and apoptosis were detected by cell viability analyzer Vi-CELL and flow cytometric analysis, respectively. We analyzed the alterations in the proteome profile of L9981 cells induced by MSA using the 2-D difference in gel electrophoresis (2-D DIGE) and identified the differentially expressed proteins using a liquid chromatography system followed by tandem mass spectrometry (LC-MS/MS).
  
  
  RESULTS
  We found that MSA inhibited cell proliferation in a dose-dependent manner and significantly induced early apoptosis in L9981 cells. 2-D DIGE showed that MSA induced significant changes (>1.29 fold) in the expression levels of 42 protein spots compared to the untreated control (P < 0.05). As identified by LC-MS/MS, proteins that underwent changes in response to MSA were related to various biological functions, including: (i) endoplasmic reticulum stress (upregulation of molecular chaperones like heat shock protein A5, protein disulfide-isomerase precursor, and calreticulin precursor); (ii) oxidative stress response/ thioredoxin system (decreased thioredoxin-like protein 1 and increased thioredoxin reductase 1); (iii) translation regulation (downregulation of translation factors like elongation factor 1-beta and eukaryotic translation initiation factor 6); (iv) mitochondrial bioenergetic function (upregulation of adenosine triphosphate synthase subunit beta and mitochondria); and (v) cell signal transduction regulation (decreased peptidyl-prolyl cis-trans isomerase A and 14-3-3 protein gamma). The protein and gene expression levels of those proteins of interest were further confirmed by Western blot and/or real-time reverse transcription polymerase chain reaction.
  
  
  CONCLUSIONS
  Our results suggest that MSA may inhibit cell proliferation and induce apoptosis in lung cancer by modulating multiple targets involved in various crucial cellular processes.
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhong
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Tan
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hou
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Nagalakshmi
authors.initials: N
authors.lastname: Nadimity
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Xingyang
authors.initials: X
authors.lastname: Xue
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
authors.affiliation: The Key Laboratory of Lung Cancer Molecular Biology in Sichuan Province, West China Hospital, Sichuan University, Sichuan, ChinaTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, ChinaGraduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California, USADepartment of Thoracic Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, ChinaDepartment of Respiratory Medicine, the Second Hospital affiliated to Dalian Medical University, Dalian, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhou
keywords: 2-D DIGE; LC-MS/MS; apoptosis; growth inhibition; lung cancer; methylseleninic acid