Chen George G, Xu Hu, Lee Janet F Y, Subramaniam Malayannan, Leung Ka L, Wang Su H, Chan Ursula P F, Spelsberg Thomas C
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Int J Cancer. 2003 Dec 10;107(5):837-43. doi: 10.1002/ijc.11447.
Peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits cell growth via promoting apoptosis. Human colorectal cancer tissues had abundant PPARgamma but the incidence of apoptosis was very low, suggesting a defect in the PPARgamma pathway. Here, we found that 15-hydroxy-eicosatetraenoic acid (15S-HETE), an endogenous ligand for PPARgamma, was significantly decreased in the serum of patients with colorectal cancer. Treatment of colon cancer cells with 15S-HETE inhibited cell proliferation and induced apoptosis, which was preceded by an increase in TGF-beta-inducible early gene (TIEG) and a decrease in Bcl-2. The action of 15S-HETE could be blocked when PPARgamma was suppressed. Overexpression of Bcl-2 prevented the apoptosis. The levels of TIEG and 15-lipoxygenase (15-LOX), the enzyme responsible for 15S-HETE production, was decreased in colorectal cancer. Therefore, colorectal cancer is associated with decreased 15S-HETE. Treatment of colon cancer cells with 15S-HETE inhibits cell proliferation and induces apoptosis in a PPARgamma-dependent pathway involving augmentation of TIEG and reduction of Bcl-2 expression.
过氧化物酶体增殖物激活受体γ（PPARγ）通过促进细胞凋亡来抑制细胞生长。人类结直肠癌组织中PPARγ含量丰富，但细胞凋亡发生率却很低，这表明PPARγ信号通路存在缺陷。在此，我们发现，作为PPARγ内源性配体的15-羟基-二十碳四烯酸（15S-HETE）在结直肠癌患者血清中显著减少。用15S-HETE处理结肠癌细胞可抑制细胞增殖并诱导细胞凋亡，这一过程先于转化生长因子-β诱导早期基因（TIEG）的增加和Bcl-2的减少。当PPARγ被抑制时，15S-HETE的作用会被阻断。Bcl-2的过表达可防止细胞凋亡。结直肠癌中TIEG和15-脂氧合酶（15-LOX，负责产生15S-HETE的酶）的水平降低。因此，结直肠癌与15S-HETE减少有关。用15S-HETE处理结肠癌细胞可通过PPARγ依赖的信号通路抑制细胞增殖并诱导细胞凋亡，该信号通路涉及TIEG的增加和Bcl-2表达的降低。
