胆固醇甾体醛诱导野生型肿瘤蛋白p53的淀粉样蛋白生成和功能障碍。
Cholesterol secosterol aldehydes induce amyloidogenesis and dysfunction of wild-type tumor protein p53.
作者信息
Nieva Jorge, Song Byeong-Doo, Rogel Joseph K, Kujawara David, Altobel Lawrence, Izharrudin Alicia, Boldt Grant E, Grover Rajesh K, Wentworth Anita D, Wentworth Paul
机构信息
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
出版信息
Chem Biol. 2011 Jul 29;18(7):920-7. doi: 10.1016/j.chembiol.2011.02.018.
Epidemiologic and clinical evidence points to an increased risk for cancer when coupled with chronic inflammation. However, the molecular mechanisms that underpin this interrelationship remain largely unresolved. Herein we show that the inflammation-derived cholesterol 5,6-secosterol aldehydes, atheronal-A (KA) and -B (ALD), but not the polyunsaturated fatty acid (PUFA)-derived aldehydes 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), induce misfolding of wild-type p53 into an amyloidogenic form that binds thioflavin T and Congo red dyes but cannot bind to a consensus DNA sequence. Treatment of lung carcinoma cells with KA and ALD leads to a loss of function of extracted p53, as determined by the analysis of extracted nuclear protein and in activation of p21. Our results uncover a plausible chemical link between inflammation and cancer and expand the already pivotal role of p53 dysfunction and cancer risk.
流行病学和临床证据表明，慢性炎症会增加患癌风险。然而，支撑这种相互关系的分子机制在很大程度上仍未得到解决。在此我们表明，炎症衍生的胆固醇5,6-甾醇醛，即动脉粥样硬化醛-A（KA）和 -B（ALD），而非多不饱和脂肪酸（PUFA）衍生的醛4-羟基壬烯醛（HNE）和4-羟基己烯醛（HHE），会诱导野生型p53错误折叠成一种淀粉样生成形式，该形式能结合硫黄素T和刚果红染料，但不能结合共有DNA序列。用KA和ALD处理肺癌细胞会导致提取的p53功能丧失，这通过对提取的核蛋白分析和p21的失活得以确定。我们的结果揭示了炎症与癌症之间一种看似合理的化学联系，并扩展了p53功能障碍与癌症风险已有的关键作用。
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