TY - JOUR
T1 - Nuclear factor-κB maintains TRAIL resistance in human pancreatic cancer cells
AU - Khanbolooki, Sanaz
AU - Nawrocki, Steffan T.
AU - Arumugam, Thiruvengadam
AU - Andtbacka, Robert
AU - Pino, Maria S.
AU - Kurzrock, Razelle
AU - Logsdon, Craig D.
AU - Abbruzzese, James L.
AU - McConkey, David J.
PY - 2006/9
Y1 - 2006/9
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-06-0075
DO - 10.1158/1535-7163.MCT-06-0075
M3 - Article
C2 - 16985059
AN - SCOPUS:33749578608
SN - 1535-7163
VL - 5
SP - 2251
EP - 2260
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -