Nuclear factor-κB maintains TRAIL resistance in human pancreatic cancer cells

Sanaz Khanbolooki, Steffan T. Nawrocki, Thiruvengadam Arumugam, Robert Andtbacka, Maria S. Pino, Razelle Kurzrock, Craig D. Logsdon, James L. Abbruzzese, David J. McConkey

Research output: Contribution to journalArticle

Abstract

Although it displays promising activity in other tumor models, the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human pancreatic cancer cells have not been comprehensively explored. We report that a majority of human pancreatic cancer cell lines (seven of nine) underwent apoptosis when they were exposed to recombinant human TRAIL in vitro. Characterization of surface TRAIL receptors by fluorescence-activated cell sorting showed that TRAIL-resistant cells (Panc-1 and HS766T) expressed lower levels of DR4 and DR5 than did TRAIL-sensitive cells. The proteasome inhibitor bortezomib (PS-341, Velcade) further increased TRAIL responsiveness in the TRAIL-sensitive cells and synergized with TRAIL to reverse resistance in Panc-1 and HS776T cells. The effects of bortezomib were mimicked by transfection with a small interfering RNA construct specific for the p65 subunit of nuclear factor-κB (NF-κB) or exposure to a selective chemical inhibitor of IKK [PS-1145). Silencing IκBα prevented TRAIL sensitization by PS-1145, confirming that IκBα mediated the effects of PS-1145. NF-κB inhibition resulted in down-regulation of BCL-XL and XIAP, and silencing either restored TRAIL sensitivity in TRAIL-resistant cells. Finally, therapy with TRAIL plus PS-1145 reversed TRAIL resistance in vivo to produce synergistic growth inhibition in orthotopic Panc-1 tumors. Together, our results show that NF-κB inhibits TRAIL-induced apoptosis in human pancreatic cancer cells and suggest that combination therapy with TRAIL and NF-κB inhibitors, such as bortezomib, PS-1145, or curcumin, should be considered as a possible treatment strategy in patients with pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)2251-2260
Number of pages10
JournalMolecular cancer therapeutics
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Khanbolooki, S., Nawrocki, S. T., Arumugam, T., Andtbacka, R., Pino, M. S., Kurzrock, R., Logsdon, C. D., Abbruzzese, J. L., & McConkey, D. J. (2006). Nuclear factor-κB maintains TRAIL resistance in human pancreatic cancer cells. Molecular cancer therapeutics, 5(9), 2251-2260. https://doi.org/10.1158/1535-7163.MCT-06-0075