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The Nuclear Factor-B RelA Transcription Factor Is Constitutively Activated in Human Pancreatic Adenocarcinoma Cells¹

Departments of Surgical Oncology [W. W., D. B. E., L. L., P. J. C.], Tumor Biology [P. J. C.], Gastrointestinal Medical Oncology and Digestive Diseases [J. L. A.], and Pathology [K. R. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Pancreatic adenocarcinoma is a leading cause of adult cancer mortality in the United States. Recent studies have revealed that point mutation of the K-ras oncogene is a common event in pancreatic cancer, and oncogenesis mediated by Ras may also involve activation of Rel/nuclear factor (NF)-B transcription factors. Furthermore, the c-rel member of Rel/NF-B transcription factor family was first identified as a cellular homologue of the v-rel oncogene, suggesting that other members of the Rel/NF-B family are potentially oncogenes. We therefore investigated the possibility that Rel/NF-B transcription factors are activated in pancreatic cancer. Immunohistochemical analysis, Western blot and Northern blot analysis, electrophoretic mobility shift assays, and chloramphenicol acetyltransferase assays were performed to determine RelA activity in human pancreatic adenocarcinomas and normal tissues and nontumorigenic or tumorigenic cell lines. RelA, the p65 subunit of NF-B, was constitutively activated in 67% (16 of 24) of pancreatic adenocarcinomas but not in normal pancreatic tissues. Constitutive RelA activity was also detected in 9 of 11 human pancreatic tumor cell lines but not in nontumorigenic Syrian golden hamster cell lines. IB, a previously identified NF-B-inducible gene, was overexpressed in human pancreatic tumor tissues and cell lines, and RelA activation could be inhibited by curcumin and dominant-negative mutants of IB, raf, and MEKK1. This is the first report demonstrating constitutive activation of RelA in nonlymphoid human cancer. These data are consistent with the possibility that RelA is constitutively activated by the upstream signaling pathway involving Ras and mitogen-activated protein kinases in pancreatic tumor cells. Constitutive RelA activity may play a key role in pancreatic tumorigenesis through activation of its downstream target genes.

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				T. R. Singh, S. Shankar, X. Chen, M. Asim, and R. K. Srivastava Synergistic Interactions of Chemotherapeutic Drugs and Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Apo-2 Ligand on Apoptosis and on Regression of Breast Carcinoma in Vivo Cancer Res., September 1, 2003; 63(17): 5390 - 5400. [Abstract] [Full Text] [PDF]

				L. V. Pham, A. T. Tamayo, L. C. Yoshimura, P. Lo, and R. J. Ford Inhibition of Constitutive NF-{kappa}B Activation in Mantle Cell Lymphoma B Cells Leads to Induction of Cell Cycle Arrest and Apoptosis J. Immunol., July 1, 2003; 171(1): 88 - 95. [Abstract] [Full Text] [PDF]

				T. Karashima, P. Sweeney, A. Kamat, S. Huang, S. J. Kim, M. Bar-Eli, D. J. McConkey, and C. P. N. Dinney Nuclear Factor-{kappa}B Mediates Angiogenesis and Metastasis of Human Bladder Cancer through the Regulation of Interleukin-8 Clin. Cancer Res., July 1, 2003; 9(7): 2786 - 2797. [Abstract] [Full Text] [PDF]

				S. Jeay, S. Pianetti, H. M. Kagan, and G. E. Sonenshein Lysyl Oxidase Inhibits Ras-Mediated Transformation by Preventing Activation of NF-{kappa}B Mol. Cell. Biol., April 1, 2003; 23(7): 2251 - 2263. [Abstract] [Full Text] [PDF]

				M. Oya, A. Takayanagi, A. Horiguchi, R. Mizuno, M. Ohtsubo, K. Marumo, N. Shimizu, and M. Murai Increased nuclear factor-{kappa}B activation is related to the tumor development of renal cell carcinoma Carcinogenesis, March 1, 2003; 24(3): 377 - 384. [Abstract] [Full Text] [PDF]

				X. Chen, K. Kandasamy, and R. K. Srivastava Differential Roles of RelA (p65) and c-Rel Subunits of Nuclear Factor {kappa}B in Tumor Necrosis Factor-related Apoptosis-inducing Ligand Signaling Cancer Res., March 1, 2003; 63(5): 1059 - 1066. [Abstract] [Full Text] [PDF]

				Y. Bayon, M. A. Ortiz, F. J. Lopez-Hernandez, F. Gao, M. Karin, M. Pfahl, and F. J. Piedrafita Inhibition of I{kappa}B Kinase by a New Class of Retinoid-Related Anticancer Agents That Induce Apoptosis Mol. Cell. Biol., February 1, 2003; 23(3): 1061 - 1074. [Abstract] [Full Text]

				S. Fujioka, G. M. Sclabas, C. Schmidt, W. A. Frederick, Q. G. Dong, J. L. Abbruzzese, D. B. Evans, C. Baker, and P. J. Chiao Function of Nuclear Factor {kappa}B in Pancreatic Cancer Metastasis Clin. Cancer Res., January 1, 2003; 9(1): 346 - 354. [Abstract] [Full Text] [PDF]

				C. L. Scaife, J. Kuang, J. C. Wills, D. B. Trowbridge, P. Gray, B. M. Manning, E. J. Eichwald, R. A. Daynes, and S. K. Kuwada Nuclear Factor {kappa}B Inhibitors Induce Adhesion-dependent Colon Cancer Apoptosis: Implications for Metastasis Cancer Res., December 1, 2002; 62(23): 6870 - 6878. [Abstract] [Full Text] [PDF]

				Y.-J. Surh More Than Spice: Capsaicin in Hot Chili Peppers Makes Tumor Cells Commit Suicide J Natl Cancer Inst, September 4, 2002; 94(17): 1263 - 1265. [Full Text] [PDF]

				A. Arlt, J. Vorndamm, S. Muerkoster, H. Yu, W. E. Schmidt, U. R. Folsch, and H. Schafer Autocrine Production of Interleukin 1{beta} Confers Constitutive Nuclear Factor {kappa}B Activity and Chemoresistance in Pancreatic Carcinoma Cell Lines Cancer Res., February 1, 2002; 62(3): 910 - 916. [Abstract] [Full Text] [PDF]

				N. Sasaki, T. Morisaki, K. Hashizume, T. Yao, M. Tsuneyoshi, H. Noshiro, K. Nakamura, T. Yamanaka, A. Uchiyama, M. Tanaka, et al. Nuclear Factor-{kappa}B p65 (RelA) Transcription Factor Is Constitutively Activated in Human Gastric Carcinoma Tissue Clin. Cancer Res., December 1, 2001; 7(12): 4136 - 4142. [Abstract] [Full Text] [PDF]

				M. L. Guzman, S. J. Neering, D. Upchurch, B. Grimes, D. S. Howard, D. A. Rizzieri, S. M. Luger, and C. T. Jordan Nuclear factor-{kappa}B is constitutively activated in primitive human acute myelogenous leukemia cells Blood, October 15, 2001; 98(8): 2301 - 2307. [Abstract] [Full Text] [PDF]

				Y. Wen, D.-H. Yan, B. Wang, B. Spohn, Y. Ding, R. Shao, Y. Zou, K. Xie, and M.-C. Hung p202, an Interferon-inducible Protein, Mediates Multiple Antitumor Activities in Human Pancreatic Cancer Xenograft Models Cancer Res., October 1, 2001; 61(19): 7142 - 7147. [Abstract] [Full Text] [PDF]

				K. R. Hess and J. L. Abbruzzese Matrix Metalloproteinase Inhibition of Pancreatic Cancer: Matching Mechanism of Action to Clinical Trial Design J. Clin. Oncol., August 1, 2001; 19(15): 3445 - 3446. [Full Text] [PDF]

				R. Romieu-Mourez, E. Landesman-Bollag, D. C. Seldin, A. M. Traish, F. Mercurio, and G. E. Sonenshein Roles of IKK Kinases and Protein Kinase CK2 in Activation of Nuclear Factor-{{kappa}}B in Breast Cancer Cancer Res., May 1, 2001; 61(9): 3810 - 3818. [Abstract] [Full Text]

				J. B. Sunwoo, Z. Chen, G. Dong, N. Yeh, C. C. Bancroft, E. Sausville, J. Adams, P. Elliott, and C. Van Waes Novel Proteasome Inhibitor PS-341 Inhibits Activation of Nuclear Factor-{{kappa}}B, Cell Survival, Tumor Growth, and Angiogenesis in Squamous Cell Carcinoma Clin. Cancer Res., May 1, 2001; 7(5): 1419 - 1428. [Abstract] [Full Text]

				S. Huang, J. B. Robinson, A. DeGuzman, C. D. Bucana, and I. J. Fidler Blockade of Nuclear Factor-{{kappa}}B Signaling Inhibits Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular Endothelial Growth Factor and Interleukin 8 Cancer Res., October 1, 2000; 60(19): 5334 - 5339. [Abstract] [Full Text]

				M. Arsura, F. Mercurio, A. L. Oliver, S. S. Thorgeirsson, and G. E. Sonenshein Role of the Ikappa B Kinase Complex in Oncogenic Ras- and Raf-Mediated Transformation of Rat Liver Epithelial Cells Mol. Cell. Biol., August 1, 2000; 20(15): 5381 - 5391. [Abstract] [Full Text]

				S. Huang, A. DeGuzman, C. D. Bucana, and I. J. Fidler Nuclear Factor-{{kappa}}B Activity Correlates with Growth, Angiogenesis, and Metastasis of Human Melanoma Cells in Nude Mice Clin. Cancer Res., June 1, 2000; 6(6): 2573 - 2581. [Abstract] [Full Text]

				S. Jeay, G. E. Sonenshein, M.-C. Postel-Vinay, and E. Baixeras Growth Hormone Prevents Apoptosis through Activation of Nuclear Factor-{kappa}B in Interleukin-3-Dependent Ba/F3 Cell Line Mol. Endocrinol., May 1, 2000; 14(5): 650 - 661. [Abstract] [Full Text]

				J. Lewis, A. Devin, A. Miller, Y. Lin, Y. Rodriguez, L. Neckers, and Z.-g. Liu Disruption of Hsp90 Function Results in Degradation of the Death Domain Kinase, Receptor-interacting Protein (RIP), and Blockage of Tumor Necrosis Factor-induced Nuclear Factor-kappa B Activation J. Biol. Chem., March 31, 2000; 275(14): 10519 - 10526. [Abstract] [Full Text] [PDF]

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