Secreted Interleukin-1α Induces a Metastatic Phenotype in Pancreatic Cancer by Sustaining a Constitutive Activation of Nuclear Factor-κB

Transcription factor nuclear factor-kappa B (NF-kappa B) is constitutively activated in most pancreatic cancer tissues and cell lines but not in normal pancreas nor in immortalized/nontumorigenic human pancreatic ductal epithelial cells. Inhibition of constitutive NF-kappa B activation in pancreatic cancer cell lines suppresses tumorigenesis and tumor metastasis. Recently, we identified autocrine secretion of proinflammatory cytokine interleukin (IL)-1 alpha as the mechanism of constitutive NF-kappa B activation in metastatic pancreatic cancer cell lines. However, the role of IL-1 alpha in determining the metastatic potential of pancreatic tumor remains to be further investigated. In the current study, we stably expressed IL-1 alpha in the nonmetastatic, IL-1 alpha-negative MiaPaCa-2 cell lines. Our results showed that the secretion of IL-1 alpha in MiaPaCa-2 cells constitutively activated NF-kappa B and increased the expression of NF-kappa B downstream genes involved in the different steps of the metastatic cascade, such as urokinase-type plasminogen activator, vascular endothelial growth factor, and IL-8. MiaPaCa-2/IL-1 alpha cells showed an enhanced cell invasion in vitro compared with parental MiaPaCa-2 cells and induced liver metastasis in an orthotopic mouse model. The metastatic phenotype induced by IL-1 alpha was inhibited by the expression of phosphorylation-defective I kappa B (I kappa B S32, 36A), which blocked NF-kappa B activation. Consistently, silencing the expression of IL-1 alpha by short hairpin RNA in the highly metastatic L3.6pI pancreatic cancer cells completely suppressed their metastatic spread. In summary, these findings showed that IL-1 alpha plays key roles in pancreatic cancer metastatic behavior through the constitutive activation of NF-kappa B. Our findings further support the possible link between inflammation and cancer and suggest that IL-1 alpha may be a potential therapeutic target for treating pancreatic adenocarcinoma. (Mol Cancer Res 2009;7(5):624-33)