Abstract
A sulfated polysaccharide of edible mushroom Antrodia cinnamomea (SPS) has been identified as a novel immunomodulatory agent. We examined the anti-cancer effects of SPS by conducting a series of in vitro studies. We found that SPS inhibits the growth of A549 and LLC1 lung cancer cells via the induction of cell cycle arrest and activation of caspase 3 and PARP. By contrast, we found that a non-sulfated polysaccharide of A. cinnamomea (NSPS) does not inhibit lung cancer cell viability. Moreover, NSPS does not induce changes in cell cycle distribution or activate apoptosis-related molecules in both A549 and LLC1 cells. High expression of transforming growth factor β (TGFβ) and TGFβ receptors (TGFRs) is correlated with lung tumorigenesis. SPS suppresses TGFβ-induced intracellular signaling events, including phosphorylation of Smad2/3, FAK, Akt, and cell migration. By contrast, non-sulfated polysaccharide (NSPS) does not exhibit the similar biological functions in both A549 and LLC1 cells. Mechanistically, we demonstrated SPS effectively reduces TGFR protein levels via induction of proteasome-dependent degradation pathway. Our study is the first to identify the pivotal role of SPS in the induction of TGFR degradation and activation of Caspase 3 and PARP, which leads to suppress viability and migration of lung cancer cells.
Keywords:
Lung cancer; Sulfated polysaccharides; Transforming growth factor β receptors (TGFRs).
Copyright © 2016 Elsevier B.V. All rights reserved.
MeSH terms
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Antineoplastic Agents / isolation & purification
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Antineoplastic Agents / pharmacology*
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Antrodia / chemistry*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / metabolism
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Fruiting Bodies, Fungal / chemistry
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Fungal Polysaccharides / isolation & purification
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Fungal Polysaccharides / pharmacology*
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Gene Expression Regulation, Neoplastic*
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Humans
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Immunologic Factors / isolation & purification
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Immunologic Factors / pharmacology*
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Proteasome Endopeptidase Complex / drug effects*
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Respiratory Mucosa / drug effects
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / pathology
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Signal Transduction
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Sulfates / chemistry
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
Substances
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Antineoplastic Agents
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Fungal Polysaccharides
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Immunologic Factors
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Receptors, Transforming Growth Factor beta
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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Sulfates
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Transforming Growth Factor beta
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Poly(ADP-ribose) Polymerases
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Focal Adhesion Kinase 1
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PTK2 protein, human
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Proto-Oncogene Proteins c-akt
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CASP3 protein, human
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Caspase 3
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Proteasome Endopeptidase Complex