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
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
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DOI：
10.1124/jpet.103.048769
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发表时间：
2003-05-01
影响因子：
3.5
通讯作者：
Hull, MA
中科院分区：
文献类型：
--
作者：
Hawcroft, G;Gardner, SH;Hull, MA
非甾体抗炎药吲哚美辛的抗结肠直肠癌活性的机制知之甚少。吲哚美辛抑制两种环氧合酶（考克斯）亚型，但它也可以通过COX非依赖性靶点发挥作用。吲哚美辛可以结合并激活转录因子过氧化物酶体增殖物激活受体（PPAR）γ。此外，天然和合成的PPARgamma配体可以在体外诱导人结直肠癌细胞的生长停滞和凋亡。因此，我们测试的假设，吲哚美辛对人结直肠癌细胞在体外的抗增殖活性是由PPARgamma依赖的作用机制解释。人结肠直肠癌细胞系SW480和HCT 116均表达功能性PPARgamma。吲哚美辛直接激活两种细胞系中的PPARgamma（HCT 116> SW 480）。显性阴性PPARgamma策略用于证明内源性PPARgamma抑制HCT 116细胞的增殖（与肿瘤抑制活性相容），但功能性PPARgamma的存在对于体外与吲哚美辛相关的抗增殖活性（或细胞周期蛋白D1蛋白的减少）不是必需的。总之，吲哚美辛（> 100 μ M）直接激活人结肠直肠癌细胞中的PPAR γ。然而，PPARgamma激活并不是吲哚美辛体外对人结直肠癌细胞的抑制活性的基础。
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) gamma. Moreover, natural and synthetic PPARgamma 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 PPARgamma-dependent mechanism of action. Human colorectal cancer cell lines SW480 and HCT116 both expressed functional PPARgamma. Indomethacin directly activated PPARgamma in both cell lines (HCT116 > SW480). A dominant-negative PPARgamma strategy was used to demonstrate that endogenous PPARgamma represses proliferation of HCT116 cells (compatible with tumor suppressor activity) but that the presence of functional PPARgamma is not necessary for the antiproliferative activity (or reduction in cyclin D1 protein) associated with indomethacin in vitro. In summary, indomethacin (> 100 muM) directly activates PPARgamma in human colorectal cancer cells. However, PPARgamma activation does not underlie the antineoplastic activity of indomethacin on human colorectal cancer cells in vitro.