Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
Biochimie. 2013 Mar;95(3):632-40. doi: 10.1016/j.biochi.2012.10.011. Epub 2012 Oct 22.
Cholesterol oxidation products, termed oxysterols, have been shown to be more reactive than unoxidized cholesterol, possessing marked pro-inflammatory and cytotoxic effects in a number of cells and tissues. Oxysterols, absorbed with the diet as products of cholesterol auto-oxidation, have recently been suggested to potentially interfere with homeostasis of the mucosal intestinal epithelium, by promoting and sustaining irreversible damage. However, the treatment of colon cancer cells with a diet-compatible mixture of oxysterols does not elicit the same responses than individual components added to the cells at the same concentrations at which they are present in the mixture. Sixty μM oxysterol mixture showed a slight pro-apoptotic effect on human colon cancer CaCo-2 cell line, evaluated in terms of caspase-3 and caspase-7 activation; conversely, 7α-hydroxycholesterol, 7β-hydroxycholesterol and 5α,6α-epoxycholesterol were identified to be able to induce a significant pro-apoptotic effect if added to cell culture singly; 7β-hydroxycholesterol had stronger action than other compounds. The enhanced production of reactive oxygen species through up-regulation of the colonic NADPH-oxidase isoform NOX1 appeared to be the key event in oxysterol-induced apoptosis in these colon cancer cells. As regards pro-inflammatory effects of oxysterols, IL-8 and MCP-1 were evaluated for their chemotactic activity. Only MCP-1 production was significantly induced by 7β-hydroxycholesterol, as well as by cholesterol and oxysterol mixture. However, oxysterol-induced inflammation appeared to be NOX1-independent, suggesting a secondary role of this enzyme in inducing inflammation in colon cancer cells. A selective cell death induced by specific oxysterols against colon cancer cells, mainly exploiting their ability to activate NOX1 in generating oxidative reactions, might represent a promising field of investigation in colorectal cancer, and might bring new insights on strategies in anticancer therapy.
胆固醇氧化产物，称为氧化固醇，已被证明比未氧化的胆固醇更具反应性，在许多细胞和组织中具有明显的促炎和细胞毒性作用。氧化固醇作为胆固醇自动氧化的产物，随饮食被吸收，最近有人提出，它们可能通过促进和维持不可逆转的损伤，潜在地干扰肠道黏膜上皮的内稳态。然而，用与饮食相容的混合氧化固醇处理结肠癌细胞，不会引起与将单个成分以与混合物中存在的浓度相同的方式添加到细胞中时相同的反应。60μM 氧化固醇混合物对人结肠癌细胞 CaCo-2 系显示出轻微的促凋亡作用，根据半胱天冬酶-3 和半胱天冬酶-7 的激活来评估；相反，7α-羟胆固醇、7β-羟胆固醇和 5α，6α-环氧胆固醇被鉴定为如果单独添加到细胞培养物中，能够诱导明显的促凋亡作用；7β-羟胆固醇的作用比其他化合物更强。通过上调结肠 NADPH 氧化酶同工型 NOX1 来增强活性氧的产生，似乎是这些结肠癌细胞中氧化固醇诱导凋亡的关键事件。关于氧化固醇的促炎作用，评估了 IL-8 和 MCP-1 的趋化活性。只有 7β-羟胆固醇以及胆固醇和氧化固醇混合物显著诱导了 MCP-1 的产生。然而，氧化固醇诱导的炎症似乎与 NOX1 无关，表明该酶在诱导结肠癌细胞炎症中起次要作用。特定的氧化固醇对结肠癌细胞的选择性细胞死亡，主要利用它们激活 NOX1 生成氧化反应的能力，可能代表结直肠癌研究的一个有前途的领域，并可能为抗癌治疗策略带来新的见解。
