This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khanbolooki, S. Articles by McConkey, D. J. Search for Related Content PubMed PubMed Citation Articles by Khanbolooki, S. Articles by McConkey, D. J.

Research Articles: Therapeutics

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

Departments of ¹ Cancer Biology and ² Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas and ³ Division of Medical Oncology "A," Regina Elena Cancer Institute, Rome, Italy

Requests for reprints: David McConkey, Department of Cancer Biology-173, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8591; Fax: 713-792-8747. E-mail: dmcconke{at}mdanderson.org

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-B (NF-B) or exposure to a selective chemical inhibitor of IKK (PS-1145). Silencing IB prevented TRAIL sensitization by PS-1145, confirming that IB mediated the effects of PS-1145. NF-B inhibition resulted in down-regulation of BCL-X_L 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-B inhibits TRAIL-induced apoptosis in human pancreatic cancer cells and suggest that combination therapy with TRAIL and NF-B inhibitors, such as bortezomib, PS-1145, or curcumin, should be considered as a possible treatment strategy in patients with pancreatic cancer. [Mol Cancer Ther 2006;5(9):2251–60]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ L. Lashinger, unpublished observations.

⁵ L. Lashinger and R. Andtbacka, under revision.

Received 2/ 9/06; revised 6/14/06; accepted 7/11/06.

This article has been cited by other articles:

				A. Shanker, A. D. Brooks, C. A. Tristan, J. W. Wine, P. J. Elliott, H. Yagita, K. Takeda, M. J. Smyth, W. J. Murphy, and T. J. Sayers Treating Metastatic Solid Tumors With Bortezomib and a Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Agonist Antibody J Natl Cancer Inst, May 7, 2008; 100(9): 649 - 662. [Abstract] [Full Text] [PDF]

				S. Baritaki, E. Suzuki, K. Umezawa, D. A. Spandidos, J. Berenson, T. R. Daniels, M. L. Penichet, A. R. Jazirehi, M. Palladino, and B. Bonavida Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells J. Immunol., May 1, 2008; 180(9): 6199 - 6210. [Abstract] [Full Text] [PDF]

				J. Voortman, T. P. Resende, M. A.I. Abou El Hassan, G. Giaccone, and F. A.E. Kruyt TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib Mol. Cancer Ther., July 1, 2007; 6(7): 2103 - 2112. [Abstract] [Full Text] [PDF]

				A. B. Kunnumakkara, S. Guha, S. Krishnan, P. Diagaradjane, J. Gelovani, and B. B. Aggarwal Curcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-{kappa}B-Regulated Gene Products Cancer Res., April 15, 2007; 67(8): 3853 - 3861. [Abstract] [Full Text] [PDF]

				T. F. Gajewski On the TRAIL Toward Death Receptor-Based Cancer Therapeutics J. Clin. Oncol., April 10, 2007; 25(11): 1305 - 1307. [Full Text] [PDF]

				M. Shrader, M. S. Pino, L. Lashinger, M. Bar-Eli, L. Adam, C. P.N. Dinney, and D. J. McConkey Gefitinib Reverses TRAIL Resistance in Human Bladder Cancer Cell Lines via Inhibition of AKT-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Cancer Res., February 15, 2007; 67(4): 1430 - 1435. [Abstract] [Full Text] [PDF]