Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB.
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.
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Davide
D
Melisi
Jiangong
J
Niu
Zhe
Z
Chang
Qianghua
Q
Xia
Bailu
B
Peng
Satoshi
S
Ishiyama
Douglas B
DB
Evans
Paul J
PJ
Chiao
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D053582:Interleukin-1alpha; D016328:NF-kappa B