Identification of an Autoregulatory Feedback Pathway Involving Interleukin-1α in Induction of Constitutive NF-κB Activation in Pancreatic Cancer Cells
We previously reported that NF-κB is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and immortalized pancreatic ductal epithelial cells. IκBαM-mediated inhibition of constitutive NF-κB activity in human pancreatic cancer cells sup...
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Published in | The Journal of biological chemistry Vol. 279; no. 16; pp. 16452 - 16462 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
16.04.2004
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Online Access | Get full text |
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Summary: | We previously reported that NF-κB is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and immortalized pancreatic ductal epithelial cells. IκBαM-mediated inhibition of constitutive NF-κB activity in human pancreatic cancer cells suppressed tumorigenesis and liver metastasis in an orthotopic nude mouse model, suggesting that constitutive NF-κB activation plays an important role in pancreatic tumor progression and metastasis. However, the underlying mechanism by which NF-κB is activated in pancreatic cancer remains to be elucidated. In this study, we found that an autocrine mechanism accounts for the constitutive activation of NF-κB in metastatic human pancreatic cancer cell lines. Further investigation showed that interleukin-1α was the primary cytokine secreted by these cells that activates NF-κB. Neutralization of interleukin-1α activity suppressed the constitutive activation of NF-κB and the expression of its downstream target gene, urokinase-type plasminogen activator, in metastatic pancreatic cancer cell lines. Our results demonstrate that regulation of interleukin-1α expression is primarily dependent on AP-1 activity, which is in part induced by signaling pathways that are epidermal growth factor receptor-dependent and -independent. In conclusion, our findings suggest a possible mechanism for the constitutive activation of NF-κB in metastatic human pancreatic cancer cells and a possible missing mechanistic link between inflammation and cancer. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M309789200 |