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CD95 and TRAF2 promote invasiveness of pancreatic cancer cells
Author(s) -
Trauzold Anna,
Röder Christian,
Sipos Bence,
Karsten Kristin,
Arlt Alexander,
Jiang Ping,
Martin-Subero Jose Ignacio,
Siegmund Daniela,
Müerköster Susanne,
Raluy Laia Pagerols,
Siebert Reiner,
Wajant Harald,
Kalthoff Holger
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2984fje
Subject(s) - pancreatic cancer , fas receptor , cancer research , apoptosis , biology , traf2 , urokinase receptor , programmed cell death , microbiology and biotechnology , endocrinology , tumor necrosis factor alpha , cancer , plasminogen activator , biochemistry , genetics , tumor necrosis factor receptor
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‐κB‐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‐κB 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‐κB 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.