Bortuzzo C, Hanif R, Kashfi K, Staiano-Coico L, Shiff S J, Rigas B
Division of Digestive Diseases, New York Hospital Medical Center of Queens, NY, USA.
Biochim Biophys Acta. 1996 May 20;1300(3):240-6. doi: 10.1016/0005-2760(96)00003-3.
Eicosanoids have been implicated in colon carcinogenesis, but very little is known on the potential role of leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) in this process; such compounds are produced by colonocytes and tumor infiltrating leukocytes. We studied the effect of LTB4, LTB4 methyl ester, LTB5, 12(R)-HETE, 12(S)-HETE and 15(S)-HETE (10(-10), 10(-8), 10(-6) M) on the proliferation rate, the cell cycle distribution, and the rate of apoptosis in HT-29 and HCT-15 human colon carcinoma cells. Our data show that LTB4, a lipoxygenase product, increased the proliferation rate of both cell lines in a time- and concentration-dependent manner. In HT-29 cells the concentration-response curve was bell-shaped (maximal effect at 10(-8) M). The proliferative effects of LTB4 in HT-29 cells were inhibited by SC-41930, a competitive antagonist of LTB4, suggesting the existence of an LTB4 receptor in epithelial cells. The methyl ester of LTB4 stimulated the proliferation of these cells, but LTB5, an isomer of LTB4 derived from eicosapentaenoic acid, did not. Of the HETEs, only 12(R)-HETE, a P-450 product, stimulated the proliferation of both cell lines; the other HETEs, all lipoxygenase products, failed to affect the proliferation of these cells. None of these eicosanoids had any effect on cell cycle distribution or apoptosis in either cell line. Taken together with our previous data showing that PGs stimulate colon cancer cell proliferation (Qiao et al. (1995) Biochim. Biophys. Acta 1258, 215-223), these findings indicate that arachidonic acid products synthesized via at least three different pathways (cyclooxygenase, lipoxygenase, P-450) may not be able to modulate the growth of colon cancer, and suggest a potential role in human colon carcinogenesis for LTB4 and 12(R)-HETE.
类二十烷酸与结肠癌发生有关，但关于白三烯（LTs）和羟基二十碳四烯酸（HETEs）在此过程中的潜在作用知之甚少；此类化合物由结肠上皮细胞和肿瘤浸润白细胞产生。我们研究了白三烯B4（LTB4）、白三烯B4甲酯、白三烯B5、12（R）-HETE、12（S）-HETE和15（S）-HETE（10⁻¹⁰、10⁻⁸、10⁻⁶ M）对HT-29和HCT-15人结肠癌细胞增殖率、细胞周期分布及凋亡率的影响。我们的数据表明，脂氧合酶产物LTB4以时间和浓度依赖性方式增加了两种细胞系的增殖率。在HT-29细胞中，浓度-反应曲线呈钟形（在10⁻⁸ M时达到最大效应）。LTB4在HT-29细胞中的增殖作用被LTB4竞争性拮抗剂SC-41930抑制，提示上皮细胞中存在LTB4受体。LTB4甲酯刺激了这些细胞的增殖，但源自二十碳五烯酸的LTB4异构体LTB5却没有。在HETEs中，只有细胞色素P-450产物12（R）-HETE刺激了两种细胞系的增殖；其他HETEs，均为脂氧合酶产物，未能影响这些细胞的增殖。这些类二十烷酸均未对任一细胞系的细胞周期分布或凋亡产生任何影响。结合我们之前的数据表明前列腺素刺激结肠癌细胞增殖（Qiao等人（1995年）《生物化学与生物物理学报》1258，215 - 223），这些发现表明通过至少三种不同途径（环氧化酶、脂氧合酶、细胞色素P-450）合成的花生四烯酸产物可能无法调节结肠癌的生长，并提示LTB4和12（R）-HETE在人类结肠癌发生中可能发挥作用。
