Brusselmans Koen, Timmermans Leen, Van de Sande Tine, Van Veldhoven Paul P, Guan Guimin, Shechter Ishaiahu, Claessens Frank, Verhoeven Guido, Swinnen Johannes V
Laboratory for Experimental Medicine and Endocrinology, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium.
J Biol Chem. 2007 Jun 29;282(26):18777-85. doi: 10.1074/jbc.M611763200. Epub 2007 May 5.
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.
细胞增殖、迁移和存活的多种信号是通过脂筏传递的，脂筏是富含鞘脂和胆固醇的膜微区。细胞可从循环中获取胆固醇，但也能通过甲羟戊酸/类异戊二烯途径从头合成胆固醇。然而，该途径有多个分支，还会产生非甾醇类异戊二烯。角鲨烯合酶（SQS）是决定向甾醇生物合成转变的酶。我们在此证明，在前列腺癌细胞中，雄激素可增强SQS的表达，使甲羟戊酸/类异戊二烯途径的中间体导向胆固醇合成。有趣的是，由此导致的胆固醇从头合成增加主要影响脂筏中的胆固醇含量，而对非脂筏胆固醇水平无影响。相反，RNA干扰介导的SQS抑制导致与脂筏相关的胆固醇减少。这些数据表明，SQS活性和胆固醇从头合成是癌细胞中膜微区相关胆固醇的决定因素。值得注意的是，敲低SQS也会减弱前列腺癌细胞的增殖并诱导其死亡。用化学SQS抑制剂扎伐司他酸A处理癌细胞时也观察到类似效果。重要的是，尽管他汀类药物的抗肿瘤作用此前被归因于抑制蛋白质异戊二烯化，但本研究表明，特异性抑制甲羟戊酸/类异戊二烯途径的胆固醇生物合成分支也会诱导癌细胞死亡。这些发现显著强调了胆固醇从头合成对癌细胞生物学的重要性，并表明SQS是抗肿瘤干预的一个潜在新靶点。
