Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells
There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a s...
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| Format: | Article |
| Language: | English |
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Wiley
2017-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2017/5958429 |
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| author | Seyung S. Chung Yong Wu Quincy Okobi Debbie Adekoya Mohammad Atefi Orette Clarke Pranabananda Dutta Jaydutt V. Vadgama |
| author_facet | Seyung S. Chung Yong Wu Quincy Okobi Debbie Adekoya Mohammad Atefi Orette Clarke Pranabananda Dutta Jaydutt V. Vadgama |
| author_sort | Seyung S. Chung |
| collection | DOAJ |
| description | There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB 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. |
| format | Article |
| id | doaj-art-01dc7324fb54459eace8820333126af7 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-01dc7324fb54459eace8820333126af72025-02-03T00:59:14ZengWileyMediators of Inflammation0962-93511466-18612017-01-01201710.1155/2017/59584295958429Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer CellsSeyung S. Chung0Yong Wu1Quincy Okobi2Debbie Adekoya3Mohammad Atefi4Orette Clarke5Pranabananda Dutta6Jaydutt V. Vadgama7Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USADivision of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USAThere are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB 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.http://dx.doi.org/10.1155/2017/5958429 |
| spellingShingle | Seyung S. Chung Yong Wu Quincy Okobi Debbie Adekoya Mohammad Atefi Orette Clarke Pranabananda Dutta Jaydutt V. Vadgama Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells Mediators of Inflammation |
| title | Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells |
| title_full | Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells |
| title_fullStr | Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells |
| title_full_unstemmed | Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells |
| title_short | Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells |
| title_sort | proinflammatory cytokines il 6 and tnf α increased telomerase activity through nf κb stat1 stat3 activation and withaferin a inhibited the signaling in colorectal cancer cells |
| url | http://dx.doi.org/10.1155/2017/5958429 |
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