Details

Autor(en) / Beteiligte

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

Titel

Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells

Ist Teil von

• Cancer biology & therapy, 2009-08, Vol.8 (16), p.1567-1576

Ort / Verlag

United States

Erscheinungsjahr

2009

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Constitutive classical NFkappaB activation has been implicated in the development of pancreatic cancer, and inhibition of classical NFkappaB signaling sensitizes pancreatic cancer cells to apoptosis. However, the role of the more recently described non-canonical NFkappaB pathway has not been specifically addressed in pancreatic cancer. The non-canonical pathway requires stabilization of NIK and IKKalpha-dependent phosphorylation and processing of NFkappaB2/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 NFkappaB-dependent genes. In contrast, each of the tumor cell lines displayed dramatically elevated levels of subsets of the non-canonical NFkappaB 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 overexpression of dominant negative IKKalpha significantly inhibited non-canonical target gene expression in BxPC-3 cells. These findings therefore demonstrate that the non-canonical NFkappaB pathway is constitutively active and functional in pancreatic cancer cells.