![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 14, Issue 7, 3041-3054, July 2003
B–dependent Activation of Cyclooxygenase-2 by Rho GTPases: Effects on Tumor Growth and Therapeutic Consequences
Department of Molecular and Cellular Biology of Cancer, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
Submitted August 28, 2002;
Revised March 6, 2003;
Accepted March 6, 2003
Monitoring Editor: Richard Assoian
Rho GTPases are overexpressed in a variety of human tumors contributing to
both tumor proliferation and metastasis. Recently, several studies demonstrate
an essential role of transcriptional regulation in Rho GTPases-induced
oncogenesis. Herein, we demonstrate that RhoA, Rac1, and Cdc42 promote the
expression of cyclooxygenase-2 (COX-2) at the transcriptional level by a
mechanism that is dependent on the transcription factor nuclear
factor-
B (NF-B), but not Stat3, a transcription factor required
for RhoA-induced tumorigenesis. With respect to RhoA, this effect is dependent
on ROCK, but not PKN. Treatment of RhoA-, Rac1-, and Cdc42-transformed
epithelial cells with Sulindac and NS-398, two well-characterized nonsteroid
antiinflammatory drugs (NSAIDs), results in growth inhibition as determined by
cell proliferation assays. Accordingly, tumor growth of RhoA-expressing
epithelial cells in syngeneic mice is strongly inhibited by NS-398 treatment.
The effect of NSAIDs over RhoA-induced tumor growth is not exclusively
dependent on COX-2 because DNA-binding of NF-B is also abolished upon
NSAIDs treatment, resulting in complete loss of COX-2 expression. Finally,
treatment of RhoA-transformed cells with Bay11-7083, a specific NF-B
inhibitor, leads to inhibition of cell proliferation. We suggest that
treatment of human tumors that overexpress Rho GTPases with NSAIDs and drugs
that target NF-B could constitute a valid antitumoral strategy.
Present address: Departamento de Bioquímica, Universidad de Las
Palmas de Gran Canaria, Islas Canarias, Spain 28029.
Corresponding author. E-mail address:
jclacal{at}iib.uam.es.
This article has been cited by other articles:
|
|
 |
|
  M. C. Garcia, D. M. Ray, B. Lackford, M. Rubino, K. Olden, and J. D. Roberts Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27 J. Biol. Chem., July 31, 2009; 284(31): 20936 - 20945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hernandez, G. Lopez-Lluch, J. A. Bernal, P. Navas, and J. A. Pintor-Toro Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90 Mol. Cancer Ther., March 1, 2008; 7(3): 474 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Polk, M. E. Ellis, J. V. Kushleika, P. L. Simmonds, and J. S. Woods RhoA regulation of NF-{kappa}B activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells Am J Physiol Cell Physiol, September 1, 2007; 293(3): C1160 - C1170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Newman and L. Mrkonjich Cyclooxygenase-2 expression in feline pancreatic adenocarcinomas J Vet Diagn Invest, November 1, 2006; 18(6): 590 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. D. Liang, S. M. Lippman, T.-T. Wu, R. Lotan, and X.-C. Xu RRIG1 Mediates Effects of Retinoic Acid Receptor {beta}2 on Tumor Cell Growth and Gene Expression through Binding to and Inhibition of RhoA. Cancer Res., July 15, 2006; 66(14): 7111 - 7118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-Y. Wei, K.-C. Huang, Y.-H. Chou, P.-F. Hsieh, K.-H. Lin, and W.-W. Lin The Role of Rho-Associated Kinase in Differential Regulation by Statins of Interleukin-1beta- and Lipopolysaccharide-Mediated Nuclear Factor {kappa}B Activation and Inducible Nitric-Oxide Synthase Gene Expression in Vascular Smooth Muscle Cells Mol. Pharmacol., March 1, 2006; 69(3): 960 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Olmsted-Davis Cox-2 RANKs high in osteoclastogenesis Blood, August 15, 2005; 106(4): 1144 - 1145. [Full Text] [PDF]
|
|
|
|
|
|
A. Ramirez de Molina, D. Gallego-Ortega, J. Sarmentero, M. Banez-Coronel, Y. Martin-Cantalejo, and J. C. Lacal Choline Kinase Is a Novel Oncogene that Potentiates RhoA-Induced Carcinogenesis Cancer Res., July 1, 2005; 65(13): 5647 - 5653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Debidda, L. Wang, H. Zang, V. Poli, and Y. Zheng A Role of STAT3 in Rho GTPase-regulated Cell Migration and Proliferation J. Biol. Chem., April 29, 2005; 280(17): 17275 - 17285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Calderon-Garciduenas, W. Reed, R. R. Maronpot, C. Henriquez-Roldan, R. Delgado-Chavez, A. Calderon-Garciduenas, I. Dragustinovis, M. Franco-Lira, M. Aragon-Flores, A. C. Solt, et al. Brain Inflammation and Alzheimer's-Like Pathology in Individuals Exposed to Severe Air Pollution Toxicol Pathol, October 1, 2004; 32(6): 650 - 658. [Abstract] [PDF]
|
|
|
|
|
|
L. Ling and P. E. Lobie RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription J. Biol. Chem., July 30, 2004; 279(31): 32737 - 32750. [Abstract] [Full Text] [PDF]
|
|
