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Carcinogenesis Advance Access originally published online on May 15, 2006
Carcinogenesis 2006 27(10):1950-1960; doi:10.1093/carcin/bgl023
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Arachidonic acid-induced gene expression in colon cancer cells

Arta M. Monjazeb, Kevin P. High2, Abbie Connoy3, Lori S. Hart, Constantinos Koumenis1 and Floyd H. Chilton4,*

Department of Cancer Biology, Wake Forest University Baptist Medical Center Medical Center Boulevard, Winston-Salem, NC 27157, USA
1 Department of Radiation Oncology, Department of Internal Medicine, Wake Forest University Baptist Medical Center Medical Center Boulevard, Winston-Salem, NC 27157, USA
2 Section of Infectious Diseases, Wake Forest University Baptist Medical Center Medical Center Boulevard, Winston-Salem, NC 27157, USA
3 Section of Molecular Medicine, Wake Forest University Baptist Medical Center Medical Center Boulevard, Winston-Salem, NC 27157, USA
4 Department of Physiology and Pharmacology, Wake Forest University Baptist Medical Center Medical Center Boulevard, Winston-Salem, NC 27157, USA

*To whom correspondence should be addressed. Tel: +1 336 713 7105; Fax: +1 336 713 7168; Email: schilton{at}wfubmc.edu

It is well documented that arachidonic acid (AA) and its metabolites are intimately linked to cancer biology. However, the downstream mechanism(s) that link AA levels to cancer cell proliferation remain to be elucidated. Initial experiments in the current study showed that exogenous AA and inhibitors of AA metabolism that lead to the accumulation of unesterified AA are cytotoxic to the colon cancer cell line, HCT-116. Additionally, exogenous AA and triacsin C, an inhibitor of AA acylation, induced apoptosis and related caspase-3 activity in a transcriptionally dependent manner. Gene array analysis revealed that both exogenous AA and triacsin C alter the expression of similar genes in HCT-116 cells. For example, both downregulate several genes with well-documented roles in cell survival and apoptotic resistance. Conversely, both upregulate genes encoding activator protein-1 (AP-1) transcription factors, which have known roles in inducing apoptosis, and genes that counteract ras (Erk/MAPK) growth signaling pathways. Real-time polymerase chain reaction and immunoblotting demonstrated that mRNA and protein levels of one of the major AP-1 transcription factors, c-Jun, is markedly elevated by exogenous AA and triacsin C. Additionally, the cyclooxygenase inhibitor, sulindac sulfide, increases c-Jun mRNA levels. Together, these studies reveal that the generation of intracellular AA and its subsequent impact on gene expression probably represents a critical step that regulates colon cancer cell proliferation.


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