期刊
MEDIATORS OF INFLAMMATION
卷 2017, 期 -, 页码 -出版社
HINDAWI LTD
DOI: 10.1155/2017/5958429
关键词
-
资金
- National Institutes of Health (NIH) [U54 CA143931, U54 MD007598, UL1TR000124]
- National Institutes of Health (NCI) [U54 CA143931, U54 MD007598, UL1TR000124, U54MD0075984]
- National Institutes of Health (NIMHD) [U54 CA143931, U54 MD007598, UL1TR000124, U54MD0075984]
- National Institutes of Health (NCATS) [U54 CA143931, U54 MD007598, UL1TR000124]
- Clinical Research Education and Career Development - NIMHD [R25 MD 007610]
- Emerging Scientist Award from the Urban Health Institute-CDU [S21 MD 000103]
- Accelerating Excellence in Translational Science Pilot [G0812D05]
- NIH/NCI [SC1CA200517]
- [U54 MD 007598]
There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-alpha, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-alpha phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-kappa B physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase ( hTERT). IL-6 and TNF-alpha stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-alpha stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-alpha-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-kappa B interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer.
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