Squalene synthase, a determinant of raft-associated cholesterol and modulator of cancer cell proliferation
Squalene synthase, a determinant of raft-associated cholesterol and modulator of cancer cell proliferation
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DOI：
10.1074/jbc.m611763200
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发表时间：
2007-06-29
影响因子：
4.8
通讯作者：
Swinnen, Johannes V.
中科院分区：
文献类型：
--
作者：
Brusselmans, Koen;Timmermans, Leen;Swinnen, Johannes V.
细胞增殖、迁移和存活的几个线索通过脂筏、富含鞘脂和胆固醇的膜微域传递。细胞从循环中获取胆固醇，但也可以通过甲氧戊酸/类异戊二烯途径从头合成胆固醇。然而，这个途径有几个分支，也产生非甾醇异戊二烯类化合物。角鲨烯合成酶(SQS)是决定转向固醇生物合成的酶。在这里，我们证明了在前列腺癌细胞中，雄激素增强了SQS的表达，使甲氧戊酸/类异戊二烯途径的中间产物通向胆固醇合成。有趣的是，由此导致的胆固醇从头合成的增加主要影响脂筏的胆固醇含量，而不影响非脂筏的胆固醇水平。相反，RNA干扰介导的SQS抑制导致RAFT相关胆固醇的减少。这些数据表明，SQS活性和从头合成胆固醇是癌细胞膜微域相关胆固醇的决定因素。值得注意的是，SQS基因敲除还可以抑制前列腺癌细胞的增殖和诱导其死亡。当用化学SQS抑制剂Zaragozic A处理癌细胞时，也观察到了类似的效果。重要的是，尽管他汀类药物的抗肿瘤作用以前被归因于抑制蛋白质的异戊二烯基化，但本研究表明，特异性地抑制甲氧戊酸/异戊二烯途径的胆固醇生物合成分支也可以诱导癌细胞死亡。这些发现明显强调了从头合成胆固醇对癌细胞生物学的重要性，并表明SQS是一个潜在的抗肿瘤干预的新靶点。
Several cues for cell proliferation, migration, and survival are transmitted through lipid rafts, membrane microdomains enriched in sphingolipids and cholesterol. Cells obtain cholesterol from the circulation but can also synthesize cholesterol de novo through the mevalonate/ isoprenoid pathway. This pathway, however, has several branches and also produces non-sterol isoprenoids. Squalene synthase (SQS) is the enzyme that determines the switch toward sterol biosynthesis. Here we demonstrate that in prostate cancer cells SQS expression is enhanced by androgens, channeling intermediates of the mevalonate/ isoprenoid pathway toward cholesterol synthesis. Interestingly, the resulting increase in de novo synthesis of cholesterol mainly affects the cholesterol content of lipid rafts, while leaving non-raft cholesterol levels unaffected. Conversely, RNA interference-mediated SQS inhibition results in a decrease of raft-associated cholesterol. These data show that SQS activity and de novo cholesterol synthesis are determinants of membrane microdomain-associated cholesterol in cancer cells. Remarkably, SQS knock down also attenuates proliferation and induces death of prostate cancer cells. Similar effects are observed when cancer cells are treated with the chemical SQS inhibitor zaragozic acid A. Importantly, although the anti-tumor effect of statins has previously been attributed to inhibition of protein isoprenylation, the present study shows that specific inhibition of the cholesterol biosynthesis branch of the mevalonate/isoprenoid pathway also induces cancer cell death. These findings significantly underscore the importance of de novo cholesterol synthesis for cancer cell biology and suggest that SQS is a potential novel target for antineoplastic intervention.