Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res 2009 May;7(5):624-33
Date
05/14/2009Pubmed ID
19435817Pubmed Central ID
PMC2856954DOI
10.1158/1541-7786.MCR-08-0201Scopus ID
2-s2.0-66349109431 (requires institutional sign-in at Scopus site) 87 CitationsAbstract
Transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB activation in pancreatic cancer cell lines suppresses tumorigenesis and tumor metastasis. Recently, we identified autocrine secretion of proinflammatory cytokine interleukin (IL)-1alpha as the mechanism of constitutive NF-kappaB activation in metastatic pancreatic cancer cell lines. However, the role of IL-1alpha in determining the metastatic potential of pancreatic tumor remains to be further investigated. In the current study, we stably expressed IL-1alpha in the nonmetastatic, IL-1alpha-negative MiaPaCa-2 cell lines. Our results showed that the secretion of IL-1alpha in MiaPaCa-2 cells constitutively activated NF-kappaB and increased the expression of NF-kappaB 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-1alpha 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-1alpha was inhibited by the expression of phosphorylation-defective IkappaB (IkappaB S32, 36A), which blocked NF-kappaB activation. Consistently, silencing the expression of IL-1alpha by short hairpin RNA in the highly metastatic L3.6pl pancreatic cancer cells completely suppressed their metastatic spread. In summary, these findings showed that IL-1alpha plays key roles in pancreatic cancer metastatic behavior through the constitutive activation of NF-kappaB. Our findings further support the possible link between inflammation and cancer and suggest that IL-1alpha may be a potential therapeutic target for treating pancreatic adenocarcinoma.
Author List
Melisi D, Niu J, Chang Z, Xia Q, Peng B, Ishiyama S, Evans DB, Chiao PJAuthor
Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlotting, Western
Cell Line, Tumor
Cell Movement
Cell Proliferation
Electrophoretic Mobility Shift Assay
Gene Expression Regulation, Neoplastic
Humans
Interleukin-1alpha
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, SCID
NF-kappa B
Neoplasm Metastasis
Neoplasm Transplantation
Pancreatic Neoplasms
Protein Binding
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Transplantation, Heterologous
Tumor Burden
