Dataset Information

Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity.

ABSTRACT:

Background

Increased levels of NF-?B are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-?B activation pathways have been implicated.

Methodology/principal findings

Here we show that activation of the alternative pathway is a source for the high basal NF-?B activity in PDAC cell lines. Increased activity of the p52/RelB NF-?B complex is mediated through stabilization and activation of NF-?B-inducing kinase (NIK). We identify proteasomal downregulation of TNF receptor-associated factor 2 (TRAF2) as a mechanism by which levels of active NIK are increased in PDAC cell lines. Such upregulation of NIK expression and activity levels relays to increased proliferation and anchorage-independent growth, but not migration or survival of PDAC cells.

Conclusions/significance

Rapid growth is one characteristic of pancreatic cancer. Our data indicates that the TRAF2/NIK/NF-?B2 pathway regulates PDAC cell tumorigenicity and could be a valuable target for therapy of this cancer.

SUBMITTER: Doppler H

PROVIDER: S-EPMC3536768 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity.

Döppler Heike H Liou Geou-Yarh GY Storz Peter P

PloS one 20130103 1

<h4>Background</h4>Increased levels of NF-κB are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-κB activation pathways have been implicated.<h4>Methodology/principal findings</h4>Here we show that activation of the alternative pathway is a source for the high basal NF-κB activity in PDAC cell lines. Increased activity of the p52/RelB NF-κB complex is mediated through stabilization and activation of NF-κB-inducing kinase (NIK). We identify proteasomal d ...[more]

PMID: 23301098

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Project description:Angiopoietin-1 (Ang-1) is a well-known endothelial growth factor, but its effects on neurons have yet to be elucidated. We show that Ang-1 is rapidly downregulated in the injured brain after controlled cortical impact (CCI), a mouse experimental traumatic brain injury (TBI) model and in etoposide-induced neuronal apoptosis in vitro. Ang-1 treatment inhibits etoposide-induced upregulation of proapoptotic B-cell lymphoma 2 (Bcl-2) family members Noxa, p53 upregulated modulator of apoptosis (Puma), Bcl-2 interacting mediator of cell death (Bim), and Bcl-2-associated X protein (Bax); reduces markers of caspase-dependent (cytochrome c release/caspase activation) and caspase-independent (apoptosis-inducing factor release) pathways; and limits neuronal cell death. Ang-1 treatment phosphorylates receptors Tunica interna endothelial cell kinase 2 (Tie2), and ?1-integrin and limits the etoposide-induced decrease in protein kinase B (Akt) activity. Blocking Tie2 and ?1-integrin signaling reduces Ang-1 neuroprotective effects. After both TBI and etoposide treatment microRNA (miR)-711 are upregulated, consistent with its putative role as a negative regulator of Ang-1. We show that miR-711 directly targets the Ang-1 messenger RNA (mRNA), decreasing Ang-1 expression. Increased levels of miR-711 and Ang-1 mRNA are found in the RNA-induced silencing complex complex site of miR-mediated degradation of target mRNAs after etoposide treatment and the miR-711mimic downregulates Ang-1. Administration of miR-711 inhibitor elevates Ang-1 after TBI whereas Ang-1 administration increases Akt activation; reduces Puma, Noxa, Bim, and Bax levels; and attenuates caspase-dependent and -independent neuronal apoptosis 24?h after TBI. Ang-1 also attenuates neuronal degeneration, increases gene expression of molecules that maintain blood-brain barrier integrity, and reduces post-traumatic lesion volume/edema 24?h after TBI. Although we only observed short-term neuroprotective effects after Ang-1 administration, miR-711-dependent downregulation of Ang-1, followed by Akt pathway inhibition, may play a role in neuronal cell death after neuronal injury in vitro and after experimental TBI.

Dataset Information

Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity.

Background

Methodology/principal findings

Conclusions/significance

Publications

Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity.

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