gms | German Medical Science

128. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

03.05. - 06.05.2011, München

A Smac Mimetic Blocks TRAIL-Induced Invasion and Metastasis of Cholangiocarcinoma Cells by Inhibition of NF-κB

Meeting Abstract

  • Christian Dominik Fingas - Mayo Clinic College of Medicine, GI Research, Rochester, MN
  • Ali Canbay - University Clinic Essen, Department of Gastroenterology and Hepatology, Essen
  • Alphonse E. Sirica - Virginia Commonwealth University School of Medicine, Division of Cellular and Molecular Pathogenesis, Richmond, VA
  • Andreas Paul - University Clinic Essen, Department of General, Visceral, and Transplantation Surgery, Essen
  • Gregory J Gores - Mayo Clinic College of Medicine, GI Research, Rochester, MN

Deutsche Gesellschaft für Chirurgie. 128. Kongress der Deutschen Gesellschaft für Chirurgie. München, 03.-06.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11dgch351

DOI: 10.3205/11dgch351, URN: urn:nbn:de:0183-11dgch3511

Published: May 20, 2011

© 2011 Fingas et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

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Introduction: Cholangiocarcinoma (CCA) remains a devastating disease with limited therapeutic options. CCA cells paradoxically express TRAIL, an apoptosis-inducing ligand which, failing to kill CCA cells, instead promotes their tumorigenicity, especially NF-κB-mediated metastasis. Smac mimetics are new proapoptotic cancer therapeutic agents, which degrade inhibitor of apoptosis proteins (IAPs). We here examined the effects of the Smac mimetic JP1584 in CCA cells in vitro and in vivo.

Materials and methods: We employed human (KMCH-1, TFK-1) and rat (BDEneu) CCA cells as well as an orthotopic, syngeneic, rodent in vivo model of CCA for this study.

Results: Despite JP1584-mediated degradation of the two IAPs cIAP-1 and cIAP-2, TRAIL failed to induce apoptosis in KMCH-1, TFK-1, and BDEneu cells, consistent with a downstream-block in apoptotic signaling. Because cIAP-1 and cIAP-2 also promote canonical NF-κB activation, the effect of JP1584 on this signaling pathway was examined. Treatment with JP1584 inhibited TRAIL-induced NF-κB activation and TRAIL-mediated upregulation of the proinvasive NF-κB target gene matrix metalloproteinase 7 (MMP7) as shown by immunoblot, immunocytochemistry, EMSA analysis and quantitative RT-PCR. JP1584 also reduced TRAIL-mediated CCA cell migration (cells/field; 8 ± 2 vs. 20 ± 2; p < 0.05) and invasion (RFU; 35 ± 2 vs. 55 ± 5; p < 0.05) in vitro. Consistent with these findings, siRNA-knockdown of MMP7 also inhibited TRAIL-induced CCA cell invasion. Finally, in a rat in vivo CCA model (BDEneu cells; Fischer 344 rats) JP1584-administration reduced extrahepatic metastases (11 % vs. 67 %; p < 0.05; Figure 1 [Fig. 1]) and MMP7 mRNA levels in tumors (relative ratio; 1 ± 0.3 vs. 4.5 ± 0.7; p < 0.05) suggesting higher cure rates after early surgical intervention in a future study (i.e., 70% rat liver resection including the tumor-bearing left lateral lobe).

Conclusion: While the Smac mimetic JP1584 does not sensitize to apoptosis, it reduces TRAIL-induced CCA cell metastatic behavior by inhibition of NF-κB. These data support the emerging concept that IAPs are prometastatic and represent targets for antimetastatic neoadjuvant and/or adjuvant therapies.