Colorectal cancer (CRC) is the third most diagnosed cancer in the western world, affecting 1 out of approximately 22 people in their lifetime. Several epidemiological studies suggest a positive association between high plasma cholesterol levels and colorectal cancer. However, the molecular mechanisms by which cholesterol may alter the risk of colorectal cancer (CRC) are ill-defined as the cholesterol lowering drugs statins do not appear to decrease a patient's risk of developing colorectal cancer. Cholesterol is metabolized to active derivatives including cholesterol oxidization products (COP), known as oxysterols, which have been shown to alter cellular proliferation. These metabolites and not cholesterol per se, may therefore affect the risk of developing colorectal cancer. The cholesterol metabolite or the oxysterol 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in the plasma and has been shown to be involved in the pathogenesis of several cancers including breast and prostate cancer. However, the role of 27-OHC in colorectal cancer has not been investigated. We treated Caco2 and SW620, two well characterized colon cancer cells with low, physiological and high concentrations of 27-OHC, and found that 27-OHC reduces cellular proliferation in these cells. We also found that the effects of 27-OHC on cell proliferation are not due to cellular cytotoxicity or apoptotic cellular death. Additionally, 27-OHC-induced reduction in cell proliferation is independent of actions on its target nuclear receptors, liver-X-receptors (LXR) and estrogen receptors (ER) activation. Instead, our study demonstrates that 27-OHC significantly decreases AKT activation, a major protein kinase involved in the pathogenesis of cancer as it regulates cell cycle progression, protein synthesis, and cellular survival. Our data shows that treatment with 27-OHC substantially decreases the activation of AKT by reducing levels of its active form, p-AKT, in Caco2 cells but not SW620 cells. All-together, our results show for the first time that the cholesterol metabolite 27-OHC reduces cell proliferation in colorectal cancer cells.

大肠癌（CRC）是西方世界第三大被诊断为癌症的疾病，一生中大约有22人受到影响。几项流行病学研究表明，血浆胆固醇水平高与结直肠癌之间存在正相关。但是，胆固醇可能改变结直肠癌（CRC）风险的分子机制尚不明确，因为降胆固醇药物他汀类药物似乎并未降低患者患结直肠癌的风险。胆固醇被代谢为活性衍生物，包括胆固醇氧化产物（COP），称为氧固醇，已显示可改变细胞增殖。这些代谢物本身不是胆固醇因此，可能会影响患大肠癌的风险。胆固醇代谢产物或氧固醇27-羟基胆固醇（27-OHC）是血浆中最丰富的氧固醇，已被证明与包括乳腺癌和前列腺癌在内的多种癌症的发病机理有关。但是，尚未研究27-OHC在大肠癌中的作用。我们用低，生理和高浓度的27-OHC处理了两个特征明确的结肠癌细胞Caco2和SW620，发现27-OHC减少了这些细胞中的细胞增殖。我们还发现27-OHC对细胞增殖的影响不是由于细胞的细胞毒性或凋亡性细胞死亡。此外，27-OHC诱导的细胞增殖减少与对其靶核受体的作用无关，肝X受体（LXR）和雌激素受体（ER）激活。相反，我们的研究表明27-OHC可显着降低AKT活化，AKT活化是癌症发病机理中的主要蛋白激酶，因为它调节细胞周期进程，蛋白质合成和细胞存活。我们的数据表明，在Caco2细胞而非SW620细胞中，用27-OHC处理可通过降低其活性形式p-AKT的水平来显着降低AKT的激活。总的来说，我们的结果首次显示胆固醇代谢物27-OHC减少了结直肠癌细胞的细胞增殖。我们的数据表明，在Caco2细胞而非SW620细胞中，用27-OHC处理可通过降低其活性形式p-AKT的水平来显着降低AKT的激活。总的来说，我们的结果首次显示胆固醇代谢物27-OHC减少了结直肠癌细胞的细胞增殖。我们的数据表明，在Caco2细胞而非SW620细胞中，通过27-OHC处理可通过降低其活性形式p-AKT的水平来显着降低AKT的激活。总的来说，我们的结果首次显示胆固醇代谢物27-OHC减少了结直肠癌细胞的细胞增殖。