CD95 and TRAF2 promote invasiveness of pancreatic cancer cells.
Pancreatic adenocarcinoma represents a tumor type with extremely poor prognosis. High apoptosis resistance and a strong invasive and early metastatic potential contribute to its highly malignant phenotype. Here we identified the death receptor adaptor molecule TRAF2 as a key player in pancreatic cancer pathophysiology. Using immunohistochemistry and Western blot analysis we found TRAF2 overexpressed in 34 of 36 pancreatic tumor samples as well as in pancreatic tumor cell lines resistant to CD95-mediated apoptosis. The high TRAF2 protein level was not related to chromosomal changes, as monitored by FISH analysis. Instead, the NF-kappaB- and MEK-signaling pathways were involved. Introduction of a TRAF2 expression vector in CD95-sensitive Colo357 cells resulted in (i) resistance to CD95-induced apoptosis; (ii) increased constitutive NF-kappaB and AP-1 activity; and (iii) higher basal secretion of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA), and IL-8, leading to increased invasiveness. High apoptosis resistance and uPA secretion could be reverted by TRAF2-specific siRNA. Stimulation of TRAF2-overexpressing cells with CD95 ligand led to induction of NF-kappaB and AP-1, enhanced IL-8- and uPA-secretion, and a further increased invasiveness. Thus, TRAF2 overexpression does not only block apoptosis induction by CD95 but also converts this death receptor into a mediator of invasiveness.
Trauzold
Anna
A
Molecular Oncology Unit, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Röder
Christian
C
Sipos
Bence
B
Karsten
Kristin
K
Arlt
Alexander
A
Jiang
Ping
P
Martin-Subero
Jose Ignacio
JI
Siegmund
Daniela
D
Müerköster
Susanne
S
Pagerols-Raluy
Laia
L
Siebert
Reiner
R
Wajant
Harald
H
Kalthoff
Holger
H
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016209:Interleukin-8 / Q000032:analysis; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis; D019014:fas Receptor / Q000502:physiology*
D016209:Interleukin-8; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D019014:fas Receptor; D020929:Mitogen-Activated Protein Kinase Kinases; D014568:Urokinase-Type Plasminogen Activator