| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
1 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina and 2 Department of Animal Sciences, North Carolina State University, Raleigh, North Carolina
Requests for reprints: Thomas Eling, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, P.O. Box 12233, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709. Phone: 919-541-3911; Fax: 919-541-0146. E-mail: Eling{at}niehs.nih.gov
We previously showed that nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide, which has chemopreventive activity, modulate the expression of several genes detected by microarray analysis. Activating transcription factor 3 (ATF3) was selected for further study because it is a transcription factor involved in cell proliferation, apoptosis, and invasion, and its expression is repressed in human colorectal tumors as compared with normal adjacent tissue. In this report, we show that ATF3 mRNA and protein expression are up-regulated in HCT-116 human colorectal cancer cells following treatment with NSAIDs, troglitazone, diallyl disulfide, and resveratrol. To ascertain the biological significance of ATF3, we overexpressed full-length ATF3 protein in the sense and antisense orientations. Overexpression of ATF3 in the sense orientation decreased focus formation in vitro and reduced the size of mouse tumor xenografts by 54% in vivo. Conversely, overexpression of antisense ATF3 was protumorigenic in vitro, however, not in vivo. ATF3 in the sense orientation did not modulate apoptosis, indicating another mechanism is involved. With microarray analysis, several genes relating to invasion and metastasis were identified by ATF3 overexpression and were confirmed by real-time reverse transcription-PCR, and several of these genes were modulated by sulindac sulfide, which inhibited invasion in these cells. Furthermore, overexpression of ATF3 inhibited invasion to a similar degree as sulindac sulfide treatment, whereas antisense ATF3 increased invasion. In conclusion, ATF3 represents a novel mechanism in which NSAIDs exert their anti-invasive activity, thereby linking ATF3 and its gene regulatory activity to the biological activity of these compounds.
Key Words: Colorectal cancer • NSAIDs • Cyclooxygenase • ATF3
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.
Received 12/16/04; revised 1/24/05; accepted 3/ 2/05.
This article has been cited by other articles:
|
|
 |
|
  C. Moser, S. A. Lang, S. Kainz, A. Gaumann, S. Fichtner-Feigl, G. E. Koehl, H. J. Schlitt, E. K. Geissler, and O. Stoeltzing Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo Mol. Cancer Ther., November 1, 2007; 6(11): 2868 - 2878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Cho, K. Yoon, S. Chintharlapalli, M. Abdelrahim, P. Lei, S. Hamilton, S. Khan, S. K. Ramaiah, and S. Safe Nur77 Agonists Induce Proapoptotic Genes and Responses in Colon Cancer Cells through Nuclear Receptor-Dependent and Nuclear Receptor-Independent Pathways Cancer Res., January 15, 2007; 67(2): 674 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bandyopadhyay, Y. Wang, R. Zhan, S. K. Pai, M. Watabe, M. Iiizumi, E. Furuta, S. Mohinta, W. Liu, S. Hirota, et al. The Tumor Metastasis Suppressor Gene Drg-1 Down-regulates the Expression of Activating Transcription Factor 3 in Prostate Cancer Cancer Res., December 15, 2006; 66(24): 11983 - 11990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Garcia, J. Gil, I. Ventoso, S. Guerra, E. Domingo, C. Rivas, and M. Esteban Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action Microbiol. Mol. Biol. Rev., December 1, 2006; 70(4): 1032 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cebrian, P. D. Pharoah, S. Ahmed, S. Ropero, M. F. Fraga, P. L. Smith, D. Conroy, R. Luben, B. Perkins, D. F. Easton, et al. Genetic variants in epigenetic genes and breast cancer risk Carcinogenesis, August 1, 2006; 27(8): 1661 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Guerra, L. A. Lopez-Fernandez, M. A. Garcia, A. Zaballos, and M. Esteban Human Gene Profiling in Response to the Active Protein Kinase, Interferon-induced Serine/threonine Protein Kinase (PKR), in Infected Cells: INVOLVEMENT OF THE TRANSCRIPTION FACTOR ATF-3 IN PKR-INDUCED APOPTOSIS J. Biol. Chem., July 7, 2006; 281(27): 18734 - 18745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lu, C. D. Wolfgang, and T. Hai Activating Transcription Factor 3, a Stress-inducible Gene, Suppresses Ras-stimulated Tumorigenesis J. Biol. Chem., April 14, 2006; 281(15): 10473 - 10481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Bottone Jr., Y. Moon, B. Alston-Mills, and T. E. Eling Transcriptional Regulation of Activating Transcription Factor 3 Involves the Early Growth Response-1 Gene J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 668 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ohuchida, K. Mizumoto, N. Ishikawa, K. Fujii, H. Konomi, E. Nagai, K. Yamaguchi, M. Tsuneyoshi, and M. Tanaka The Role of S100A6 in Pancreatic Cancer Development and Its Clinical Implication as a Diagnostic Marker and Therapeutic Target Clin. Cancer Res., November 1, 2005; 11(21): 7785 - 7793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Moon, F. G. Bottone Jr., M. F. McEntee, and T. E. Eling Suppression of tumor cell invasion by cyclooxygenase inhibitors is mediated by thrombospondin-1 via the early growth response gene Egr-1 Mol. Cancer Ther., October 1, 2005; 4(10): 1551 - 1558. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
