期刊
CANCER SCIENCE
卷 103, 期 2, 页码 317-324出版社
WILEY
DOI: 10.1111/j.1349-7006.2011.02133.x
关键词
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类别
资金
- Japanese Ministry of Education, Culture, Sports, Science and Technology [21791260]
- Keio University, Tokyo, Japan
- Grants-in-Aid for Scientific Research [23791499, 21791260] Funding Source: KAKEN
Transforming growth factor-beta (TGF-beta) is involved in the regulation of cell proliferation, differentiation, and apoptosis and is associated with epithelialmesenchymal transition (EMT). Inhibition of the TGF-beta pathway is an attractive strategy for the treatment of cancer. We recently screened for novel TGF-beta inhibitors among commercially available drugs and identified protein-bound polysaccharide (PSK) as a strong inhibitor of the TGF-beta-induced reporter activity of 3TP-lux, a TGF-beta 1-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-beta pathway target genes. E-cadherin and vimentin immunohistochemistry showed that PSK suppressed TGF-beta 1-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-beta-inhibiting activity of PSK and suggest that PSK can effectively treat diseases associated with TGF-beta signaling. (Cancer Sci 2012; 103: 317324)
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