Carcinogenesis Advance Access published online on May 15, 2006
Carcinogenesis, doi:10.1093/carcin/bgl023
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1 Department of Cancer Biology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157
* To whom correspondence should be addressed. 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 down-regulate several genes with well documented roles in cell survival and apoptotic resistance. Conversely, both up regulate genes encoding AP-1 transcription factors, which have known roles in inducing apoptosis, and genes which counteract ras (Erk/MAPK) growth signaling pathways. Realtime PCR 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-2 inhibitor, sulindac sulfide, increase c-Jun mRNA levels. Together, these studies reveal that the generation of intracellular AA and its subsequent impact on gene expression likely represents a critical step that regulates colon cancer cell proliferation.
Received October 25, 2005
Revised February 28, 2006
Accepted March 18, 2006
CANCER BIOLOGY
Arachidonic acid induced gene expression in colon cancer cells
Arta M. Monjazeb 1,
Kevin P. High 2,
Abbie Connoy 3,
Lori S. Hart 1,
Constantinos Koumenis 4,
and
Floyd H. Chilton 5 *
2 Department of Internal Medicine, Section of Infectious Diseases, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157
3 Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157
4 Department of Radiation Oncology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157
5 Department of Physiology and Pharmacology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157
Floyd H. Chilton, E-mail: schilton{at}wfubmc.edu
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