Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells.
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.
Khanbolooki
Sanaz
S
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Nawrocki
Steffan T
ST
Arumugam
Thiruvengadam
T
Andtbacka
Robert
R
Pino
Maria S
MS
Kurzrock
Razelle
R
Logsdon
Craig D
CD
Abbruzzese
James L
JL
McConkey
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D006575:Heterocyclic Compounds, 3-Ring; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C456319:PS1145; D011719:Pyrazines; D011725:Pyridines; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib