Identification of an autoregulatory feedback pathway involving interleukin-1alpha in induction of constitutive NF-kappaB activation in pancreatic cancer cells.
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.
Niu
Jiangong
J
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Li
Zhongkui
Z
Peng
Bailu
B
Chiao
Paul J
PJ
D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D007375:Interleukin-1; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D066246:ErbB Receptors