Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells

Abstract

The mechanism of the anticolorectal cancer activity of the nonsteroidal anti-inflammatory drug indomethacin is poorly understood. Indomethacin inhibits both cyclooxygenase (COX) isoforms, but it may also act via COX-independent targets. Indomethacin can bind and activate the transcription factor peroxisome proliferator-activated receptor (PPAR) ␥. Moreover, natural and synthetic PPAR␥ ligands can induce growth arrest and apoptosis of human colorectal cancer cells in vitro. Therefore, we tested the hypothesis that the antiproliferative activity of indomethacin on human colorectal cancer cells in vitro is explained by a PPAR␥-dependent mechanism of action. Human colorectal cancer cell lines SW480 and HCT116 both expressed functional PPAR␥. Indomethacin directly activated PPAR␥ in both cell lines (HCT116 Ͼ SW480). A dominantnegative PPAR␥ strategy was used to demonstrate that endogenous PPAR␥ represses proliferation of HCT116 cells (compatible with tumor suppressor activity) but that the presence of functional PPAR␥ is not necessary for the antiproliferative activity (or reduction in cyclin D1 protein) associated with indomethacin in vitro. In summary, indomethacin (Ͼ100 M) directly activates PPAR␥ in human colorectal cancer cells. However, PPAR␥ activation does not underlie the antineoplastic activity of indomethacin on human colorectal cancer cells in vitro.A substantial body of evidence exists that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticolorectal cancer (CRC) activity (Shiff and Rigas, 1997;Garcia Rodriguez and Huerta-Alvarez, 2001). However, the mechanism(s) of the antineoplastic activity of this class of drugs remains unclear. It is well recognized that the majority of NSAIDs inhibit one or both of the cyclooxygenase (COX)

Peroxisome Proliferator-Activated Receptor-γ Contributes to the Inhibitory Effects of Embelin on Colon Carcinogenesis

“…This construct had been confirmed to efficiently block the function of PPARg in HCT116 cells (24). As shown in Fig.…”

EP1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

“…6 However, there are contradictory reports on which EP receptor(s) that mediate effects by PGE 2 , where some reports claim that main effects are mediated mainly through nuclear receptors, (PPARs), although some evidence suggests that PPAR activation does not explain antiproliferative effects by NSAIDs. [33][34][35] Genetic deletion/inhibition of EP receptors and the use of antagonists/agonists have concluded that EP 1 and EP 4 , but not EP 2 and EP 3 , reduced colon adenoma formation in mice. 26,27 On the other hand, studies of mRNA expression in rat colon carcinogenesis showed overexpression of EP 1 and EP 2 , but not of EP 3 and EP 4 when compared to normal colon mucosa.…”

Review article: the potential of combinational regimen with non-steroidal anti-inflammatory drugs in the chemoprevention of colorectal cancer

“…Secondly, a number of NSAIDs, including indometacin, have been shown to behave as PPAR γ ligands 64 . The antineoplastic effects of the NSAID indometacin in vitro , however, do not seem to be mediated through PPAR γ 65, 66 . Thirdly, the COX‐2 promoter contains a peroxisome proliferator response element that can bind PPAR γ ligands 67 .…”