[PDF][PDF] Constitutive noncanonical NFκB signaling in pancreatic cancer cells

CE Wharry, KM Haines, RG Carroll… - Cancer biology & …, 2009 - Taylor & Francis
CE Wharry, KM Haines, RG Carroll, MJ May
Cancer biology & therapy, 2009Taylor & Francis
Constitutive classical NF-κB activation has been implicated in the development of pancreatic
cancer, and inhibition of classical NF-κB signaling sensitizes pancreatic cancer cells to
apoptosis. However, the role of the more recently described non-canonical NF-κB pathway
has not been specifically addressed in pancreatic cancer. The non-canonical pathway
requires stabilization of NIK and IKKα-dependent phosphorylation and processing of NF-
κB2/p100 to p52. This leads to the activation of p52-RelB heterodimers that regulate genes …
Constitutive classical NF-κB activation has been implicated in the development of
pancreatic cancer, and inhibition of classical NF-κB signaling sensitizes pancreatic cancer cells
to apoptosis. However, the role of the more recently described non-canonical NF-κB pathway
has not been specifically addressed in pancreatic cancer. The non-canonical pathway requires
stabilization of NIK and IKKα-dependent phosphorylation and processing of NF-κB2/p100 to
p52. This leads to the activation of p52-RelB heterodimers that regulate genes encoding
lymphoid-specific chemokines and cytokines. We performed qRT-PCR to detect gene expression
in a panel of pancreatic ductal adenocarcinoma cell lines (BxPC-3, PCA-2, PANC-1, Capan-1,
Hs-766T, AsPC-1, MiaPACA-2) and found only modest elevation of classical NF-κB-dependent
genes. In contrast, each of the tumor cell lines displayed dramatically elevated levels of subsets
of the non-canonical NF-κB target genes CCL19, CCL21, CXCL12, CXCL13 and BAFF.
Consistent with activation of the non-canonical pathway, p52 and RelB co-localized in
adenocarcinoma cells in sections of pancreatic tumor tissue, and each of the tumor cell lines
displayed elevated p52 levels. Furthermore, p52 and RelB co-immunoprecipitated from
pancreatic cancer cells and immunoblotting revealed that NIK was stabilized and p100 was
constitutively phosphorylated in a subset of the cell lines. Finally, stable over expression of
dominant negative IKKα significantly inhibited non-canonical target gene expression in BxPC-3
cells. These findings therefore demonstrate that the non-canonical NF-κB pathway is
constitutively active and functional in pancreatic cancer cells.
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