Identification of an Autoregulatory Feedback Pathway Involving Interleukin-1α in Induction of Constitutive NF-κB Activation in Pancreatic Cancer Cells

Abstract

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.