Direct inhibition of the transforming growth factor-β pathway by protein-bound polysaccharide through inactivation of Smad2 signaling
| Autor: | Kazuhiro Miyao, Minoru Tanabe, Yoshihiro Ono, Ayano Konagai, Masaki Kitajima, Shigeyuki Kawachi, Hiromitsu Jinno, Tetsu Hayashida, Hirotoshi Hasegawa, Hiroshi Okazaki, Yuko Kitagawa, Masahiro Shinoda |
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| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Epithelial-Mesenchymal Transition medicine.medical_treatment Apoptosis SMAD Smad2 Protein Biology Cell Movement Transforming Growth Factor beta Cell Line Tumor Chlorocebus aethiops medicine Animals Humans Vimentin Cell growth Growth factor CD24 Antigen Cell Differentiation General Medicine Cadherins Molecular biology HEK293 Cells Hyaluronan Receptors Oncology Mechanism of action COS Cells Cancer research Phosphorylation Proteoglycans medicine.symptom Mitogen-Activated Protein Kinases Transforming growth factor Signal Transduction |
| Zdroj: | Cancer science. 103(2) |
| ISSN: | 1349-7006 |
| Popis: | Transforming growth factor-β (TGF-β) is involved in the regulation of cell proliferation, differentiation, and apoptosis and is associated with epithelial-mesenchymal transition (EMT). Inhibition of the TGF-β pathway is an attractive strategy for the treatment of cancer. We recently screened for novel TGF-β inhibitors among commercially available drugs and identified protein-bound polysaccharide (PSK) as a strong inhibitor of the TGF-β-induced reporter activity of 3TP-lux, a TGF-β1-responsive luciferase reporter. Protein-bound polysaccharide is used as a non-specific immunostimulant for the treatment of gastric and colorectal cancers in Japan. The anticancer activity of this agent may involve direct regulation of growth factor production and enzyme activity in tumors in addition to its immunomodulatory effect. Although several clinical studies have shown the beneficial therapeutic effects of PSK on various types of tumors, its mechanism of action is not clear. In the present study, Western blot analysis showed that PSK suppressed the phosphorylation and nuclear localization of the Smad2 protein, thereby suggesting that PSK inhibits the Smad and MAPK pathways. Quantitative PCR analysis showed that PSK decreased the expression of several TGF-β pathway target genes. E-cadherin and vimentin immunohistochemistry showed that PSK suppressed TGF-β1-induced EMT, and FACS analysis showed that PSK inhibited the EMT-mediated generation of CD44(+) /CD24(-) cells. These data provide new insights into the mechanisms mediating the TGF-β-inhibiting activity of PSK and suggest that PSK can effectively treat diseases associated with TGF-β signaling. |
| Databáze: | OpenAIRE |
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