Faculty Collaboration Database

Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther 2006 Sep;5(9):2251-60

Date

09/21/2006

Pubmed ID

16985059

DOI

10.1158/1535-7163.MCT-06-0075

Scopus ID

2-s2.0-33749578608 (requires institutional sign-in at Scopus site)   124 Citations

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-kappaB (NF-kappaB) or exposure to a selective chemical inhibitor of IKK (PS-1145). Silencing IkappaBalpha prevented TRAIL sensitization by PS-1145, confirming that IkappaBalpha mediated the effects of PS-1145. NF-kappaB 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-kappaB inhibits TRAIL-induced apoptosis in human pancreatic cancer cells and suggest that combination therapy with TRAIL and NF-kappaB inhibitors, such as bortezomib, PS-1145, or curcumin, should be considered as a possible treatment strategy in patients with pancreatic cancer.

Author List

Khanbolooki S, Nawrocki ST, Arumugam T, Andtbacka R, Pino MS, Kurzrock R, Logsdon CD, Abbruzzese JL, McConkey DJ

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Boronic Acids
Bortezomib
Drug Synergism
Heterocyclic Compounds, 3-Ring
Humans
I-kappa B Proteins
Male
Mice
Mice, Inbred BALB C
Mice, Nude
NF-KappaB Inhibitor alpha
NF-kappa B
Pancreatic Neoplasms
Pyrazines
Pyridines
RNA, Small Interfering
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor
Recombinant Proteins
TNF-Related Apoptosis-Inducing Ligand
Xenograft Model Antitumor Assays