Molecular mechanism of Antrodia cinnamomea sulfated polysaccharide on the suppression of lung cancer cell growth and migration via induction of transforming growth factor β receptor degradation.
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.
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan. Electronic address: mklu@nricm.edu.tw.
Mei-Kuang
MK
Lu
Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
Tung-Yi
TY
Lin
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
Chi-Hsein
CH
Chao
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
Chun-Hao
CH
Hu
Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan; The Genomics Research Center, Academia Sinica, Taipei, Taiwan. Electronic address: hsienyeh@gmail.com.
Hsien-Yeh
HY
Hsu
D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D055491:Antrodia / Q000737:chemistry*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D048690:Fruiting Bodies, Fungal / Q000737:chemistry; D062610:Fungal Polysaccharides / Q000302:isolation & purification / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors / Q000302:isolation & purification / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013431:Sulfates / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D062610:Fungal Polysaccharides; D007155:Immunologic Factors; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D013431:Sulfates; D016212:Transforming Growth Factor beta; D011065:Poly(ADP-ribose) Polymerases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex
Lung cancer; Sulfated polysaccharides; Transforming growth factor β receptors (TGFRs)