NEW YORK (Reuters Health) - The peroxisome proliferator-activated receptor (PPAR)-delta mediates the colorectal adenoma growth induced by prostaglandin E2 (PGE2), according to a report in the September issue of Cancer Cell.
Prostaglandin E2 and PPAR-delta are both known to promote cell survival and affect carcinoma growth in vitro, the authors explain, but how they interact has not been reported.
Dr. Raymond N. DuBois from Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues used human colon carcinoma cells in culture and a mouse model to test their hypothesis that the ability of PGE2 to accelerate adenomatous polyp growth depends on PPAR-delta.
In human colon carcinoma cells, the authors report, PGE2 increased transcription of PPAR-delta by way of the PI3K/Akt cascade, indicating that PPAR-delta is an important downstream mediator of PGE2.
In these cell cultures, PGE2-mediated cell survival also required activation of PPAR-delta.
In a mouse model of intestinal adenoma, the researchers note, exogenous administration of PGE2 increased colorectal and small intestinal polyp burden and decreased the number of apoptotic cells. These findings did not occur in mice lacking PPAR-delta.
“Our data linking the COX pathway to PPAR-delta suggest that the receptor is an integral component of the crosstalk that occurs between multiple pro-oncogenic signaling pathways during the shift in balance between cell survival and cell death that promotes colorectal carcinogenesis,” the investigators conclude.
“We are in the process of developing and testing a PPAR-delta receptor antagonist to determine whether this would be effective in preventing cancer or polyp formation in mice,” Dr. DuBois told Reuters Health.
However, “Patients with familial adenomatous polyposis may want to avoid taking PPAR-delta receptor agonists until this has been studied more carefully to determine whether these effects in mice are predictive of what will happen in humans,” Dr. DuBois added.
Source: Cancer Cell 2004;6:285-295. [ Google search on this article ]
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