Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells.

Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Research Abstract Details 

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Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Abstract Text:

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

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.

Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Publishing Authors By Initials

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

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Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular cancer therapeutics

VOLUME: 5

Page Numbers: 2251-60

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ISSN: 1535-7163

DAY: 3

MONTH: Sep

YEAR: 2006

Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells.

AFFILIATION: Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Country: United States

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MEDLINETA: Mol Cancer Ther

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