Abstract
We previously reported that NF-kappaB is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and immortalized pancreatic ductal epithelial cells. IkappaBalphaM-mediated inhibition of constitutive NF-kappaB activity in human pancreatic cancer cells suppressed tumorigenesis and liver metastasis in an orthotopic nude mouse model, suggesting that constitutive NF-kappaB activation plays an important role in pancreatic tumor progression and metastasis. However, the underlying mechanism by which NF-kappaB 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-kappaB in metastatic human pancreatic cancer cell lines. Further investigation showed that interleukin-1alpha was the primary cytokine secreted by these cells that activates NF-kappaB. Neutralization of interleukin-1alpha activity suppressed the constitutive activation of NF-kappaB 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-1alpha 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-kappaB in metastatic human pancreatic cancer cells and a possible missing mechanistic link between inflammation and cancer.
Highlights
NF-B is a family of pleiotropic transcription factors that control the expression of numerous genes involved in growth, tumorigenesis, tumor metastasis, differentiation, embryonic development, apoptosis, and inflammation [1,2,3,4]
Our more recent work showed that inhibition of constitutive NF-B activity by a mutant IB␣ (S32A,S36A) completely suppressed the liver metastasis of the pancreatic cancer cell line ASPC-1 and the tumorigenic phenotype of a nonmetastatic pancreatic tumor cell line, PANC-1, suggesting that constitutive RelA activity plays a key role in pancreatic cancer metastasis and tumor progression [19, 20]
Our results show that overexpression of IL-1␣ is primarily induced by AP-1 activity, which is partially dependent on the overexpression of epidermal growth factor receptor (EGFR) in several metastatic pancreatic cancer cell lines but not in nonmetastatic pancreatic cancer cell lines
Summary
NF-B is a family of pleiotropic transcription factors that control the expression of numerous genes involved in growth, tumorigenesis, tumor metastasis, differentiation, embryonic development, apoptosis, and inflammation [1,2,3,4]. Our results showed that the conditioned medium from ASPC-1 and MDAPanc-28 pancreatic cancer cell lines induced NF-B activation in a time-dependent mode but did not increase Oct-1 DNA binding activity (Fig. 1A).
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