title: A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro.
abstract: BACKGROUND
  The proteasome exists in all eukaryotic cells and provides the main route of intracellular proteins degradation involved in cell growth and apoptosis. Proteasome inhibition could block protein degradation pathways and disturb regulatory networks, possibly leading to profound effects on cell growth, particularly in cancer cells. A proteasome inhibitor with an appropriate toxicity index for malignant cells rather than normal cells would be an attractive anticancer therapy.
  
  
  METHODS
  The human osteosarcoma (OS) cell lines MG-63 and Saos-2 and normal osteoblast cells were used to study the antitumour activity of the proteasome inhibitor MLN9708/2238.
  
  
  RESULTS
  MLN2238 inhibited cell growth, induced cell cycle arrest and apoptosis, and attenuated the invasion abilities of MG-63 and Saos-2 cells, with little cytotoxicity to normal cells. In addition, MLN2238 promoted antitumour mechanisms including the accumulation of E2F1, P53, P21 and other negative G2/M checkpoint proteins; up-regulated the relative expression ratio of BAX/BCL-2, APAF-1 and pro-apoptotic proteins of the BCL-2 family; triggered mitochondrial outer membrane permeabilization (MOMP); down-regulated BCL-2 and XIAP; activated caspase3/8/9; and suppressed MMP2/9 expression and secretion levels.
  
  
  CONCLUSIONS
  The proteasome may be a novel biochemical target for OS treatment in vitro. Our study provides a promising mechanistic framework for MLN9708/2238 in OS treatment, supporting its clinical development.
authors.forename: Renhao
authors.initials: R
authors.lastname: Liu
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Fu
authors.forename: Jiabing
authors.initials: J
authors.lastname: Sun
authors.forename: Xvming
authors.initials: X
authors.lastname: Wang
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Wang
authors.forename: Jilong
authors.initials: J
authors.lastname: Zou
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Bi
authors.forename: Chenglin
authors.initials: C
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001896:Boron Compounds / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001896:Boron Compounds; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000595706:MLN2238; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C548400:ixazomib; D046988:Proteasome Endopeptidase Complex; D005998:Glycine
keywords: Apoptosis; Cell cycle arrest; Cell invasion; MLN9708/2238; Mitochondria; Osteosarcoma (OS); Proteasome; Proteasome inhibitor; Protein homeostasis