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Research Paper

Constitutive noncanonical NFκB signaling in pancreatic cancer cells

Catherine E. Wharry, Kathleen M. Haines, Richard G. Carroll and Michael J. May

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.

Authors

Catherine E. Wharry

University of Pennsylvania, School of Veterinary Medicine

Kathleen M. Haines

Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Richard G. Carroll

Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Michael J. May

Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104; Mari Lowe Center for Comparative Oncology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104.