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-B is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and immortalized pancreatic ductal epithelial cells. IB␣M-mediated inhibition of constitutive NF-B activity in human pancreatic cancer cells suppressed tumorigenesis and liver metastasis in an orthotopic nude mouse model, suggesting that constitutive NF-B activation plays an important role in pancreatic tumor progression and metastasis. However, the underlying mechanism by which NF-B 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-B in metastatic human pancreatic cancer cell lines. Further investigation showed that interleukin-1␣ was the primary cytokine secreted by these cells that activates NF-B. Neutralization of interleukin-1␣ activity suppressed the constitutive activation of NF-B and the expression of its downstream target gene, urokinasetype plasminogen activator, in metastatic pancreatic cancer cell lines. Our results demonstrate that regulation of interleukin-1␣ 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-B in metastatic human pancreatic cancer cells and a possible missing mechanistic link between inflammation and cancer.

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

“…This is what we found with two antimelanoma CTL clones, including a CTL recognizing the immunodominant peptide Melan-A/MART1 [26][27][28][29][30][31][32][33][34][35] , presented by HLA-A2. In a previous study, IFN-c was shown to reduce by up to 78% the cytotoxicity of anti-Melan-A/MART-1 26-35 CTL, despite the stimulatory effect of IFN-c on MHC class I expression and antigen presentation.…”

“…In a previous study, IFN-c was shown to reduce by up to 78% the cytotoxicity of anti-Melan-A/MART-1 26-35 CTL, despite the stimulatory effect of IFN-c on MHC class I expression and antigen presentation. 22 This reduction is most likely due to the induction of the immunoproteasome, which does not process the Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] peptide. 42 Data of a recent study suggest that IL-1b is not able to induce the immunoproteasome.…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Mechanisms of NF-kB activation in pancreatic cancer appear to involve K-Ras and Akt activation, as well as Notch-1 signaling, nuclear glycogen synthase kinase-3b, and Vav1 (Wang et al, 1999c(Wang et al, , 2006Asano et al, 2004;Fernandez-Zapico et al, 2005;Ougolkov et al, 2005). Additionally, it has been reported that autocrine production of IL-1a regulates NF-kB activation in pancreatic cancer cells (Niu et al, 2004). NF-kB-regulated gene targets that encode proteins potentially relevant to the maintenance and invasion of pancreatic cancer cells are proposed to be GADD45a and urokinase-type plasminogen activator (Wang et al, 1999b;Schneider et al, 2006).…”

Mutagenesis by reversible promoter insertion to study the activation of NF-κB

“…We have previously reported that elevated secretion of certain growth factors can cause constitutive NF-B activation in many cancer cell lines, and probably, also in tumors (13,14). Others have reported that Ap1 causes elevated growth factor secretion and the ensuing activation of NF-B which, in turn, cooperates with Ap1 (25). In that case, however, the cycle only partially depended on NF-B because its inhibition failed to curtail Ap-1 activity.…”