| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B Activation through Inhibition of Activation of IB
Kinase and Akt in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of COX-2 Synthesis1
Departments of
*
Bioimmunotherapy and
Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-
B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-B. In the present study, we investigated the effect of this drug on the activation of NF-B by a wide variety of agents. We found that celecoxib suppressed NF-B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1
. Celecoxib inhibited TNF-induced IB
kinase activation, leading to suppression of IB phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with IB kinase (IKK). Celecoxib abrogated the NF-B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
This article has been cited by other articles:
|
|
 |
|
  U. Grandel, D. Heygster, U. Sibelius, L. Fink, S. Sigel, W. Seeger, F. Grimminger, and K. Hattar Amplification of Lipopolysaccharide-Induced Cytokine Synthesis in Non-Small Cell Lung Cancer/Neutrophil Cocultures Mol. Cancer Res., October 1, 2009; 7(10): 1729 - 1735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. M. Kim, E. J. Lee, S.-Y. Park, K. H. Cho, J. Y. Kim, and H. Pyo Cyclooxygenase-2 Up-Regulates Ataxia Telangiectasia and Rad3 Related through Extracellular Signal-Regulated Kinase Activation Mol. Cancer Res., July 1, 2009; 7(7): 1158 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hu, G. Peluffo, H. Chen, R. Gelman, S. Schnitt, and K. Polyak Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast PNAS, March 3, 2009; 106(9): 3372 - 3377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Song, N. Mazurek, C. Liu, Y. Sun, Q. Q. Ding, K. Liu, M.-C. Hung, and R. S. Bresalier Galectin-3 Mediates Nuclear {beta}-Catenin Accumulation and Wnt Signaling in Human Colon Cancer Cells by Regulation of Glycogen Synthase Kinase-3{beta} Activity Cancer Res., February 15, 2009; 69(4): 1343 - 1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chittezhath, G. Deep, R. P. Singh, C. Agarwal, and R. Agarwal Silibinin inhibits cytokine-induced signaling cascades and down-regulates inducible nitric oxide synthase in human lung carcinoma A549 cells Mol. Cancer Ther., July 1, 2008; 7(7): 1817 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Sprague, B. D. Elzey, S. A. Crist, T. J. Waldschmidt, R. J. Jensen, and T. L. Ratliff Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles Blood, May 15, 2008; 111(10): 5028 - 5036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Song, S. Guha, K. Liu, N. S Buttar, and R. S Bresalier COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett's oesophagus and oesophageal adenocarcinoma Gut, November 1, 2007; 56(11): 1512 - 1521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Stasinopoulos, D. R. O'Brien, F. Wildes, K. Glunde, and Z. M. Bhujwalla Silencing of Cyclooxygenase-2 Inhibits Metastasis and Delays Tumor Onset of Poorly Differentiated Metastatic Breast Cancer Cells Mol. Cancer Res., May 1, 2007; 5(5): 435 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zhang, J. Li, K. Wu, W. Ouyang, J. Ding, Z.-g. Liu, M. Costa, and C. Huang JNK1, but not JNK2, is required for COX-2 induction by nickel compounds Carcinogenesis, April 1, 2007; 28(4): 883 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lilenbaum, M. A. Socinski, N. K. Altorki, L. L. Hart, R. S. Keresztes, S. Hariharan, M. E. Morrison, R. Fayyad, and P. Bonomi Randomized Phase II Trial of Docetaxel/Irinotecan and Gemcitabine/Irinotecan With or Without Celecoxib in the Second-Line Treatment of Non-Small-Cell Lung Cancer J. Clin. Oncol., October 20, 2006; 24(30): 4825 - 4832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Miyamoto, S. Miyake, M. Mizuno, N. Oka, S. Kusunoki, and T. Yamamura Selective COX-2 inhibitor celecoxib prevents experimental autoimmune encephalomyelitis through COX-2-independent pathway Brain, August 1, 2006; 129(8): 1984 - 1992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Yance Jr and S. M. Sagar Targeting Angiogenesis With Integrative Cancer Therapies Integr Cancer Ther, March 1, 2006; 5(1): 9 - 29. [Abstract] [PDF]
|
|
|
|
|
|
Y. Gazitt Not all that glitters is gold Blood, December 15, 2005; 106(13): 4025 - 4026. [Full Text] [PDF]
|
|
|
|
|
|
A. Kardosh, N. Soriano, Y.-T. Liu, J. Uddin, N. A. Petasis, F. M. Hofman, T. C. Chen, and A. H. Schonthal Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib Blood, December 15, 2005; 106(13): 4330 - 4338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ali, B. F. El-Rayes, F. H. Sarkar, and P. A. Philip Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy Mol. Cancer Ther., December 1, 2005; 4(12): 1943 - 1951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Karlsson, U. Huss, A. Jenner, B. Halliwell, L. Bohlin, and J. J. Rafter Human Fecal Water Inhibits COX-2 in Colonic HT-29 Cells: Role of Phenolic Compounds J. Nutr., October 1, 2005; 135(10): 2343 - 2349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H M. Prince, L. Mileshkin, A. Roberts, V. Ganju, C. Underhill, J. Catalano, R. Bell, J. F. Seymour, D. Westerman, P. J. Simmons, et al. A Multicenter Phase II Trial of Thalidomide and Celecoxib for Patients with Relapsed and Refractory Multiple Myeloma Clin. Cancer Res., August 1, 2005; 11(15): 5504 - 5514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steffel, M. Hermann, H. Greutert, S. Gay, T. F. Luscher, F. Ruschitzka, and F. C. Tanner Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH2 Kinase Phosphorylation Circulation, April 5, 2005; 111(13): 1685 - 1689. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
