Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness.
Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness.
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DOI：
10.1016/j.cmet.2014.01.019
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发表时间：
2014-03-04
期刊：
影响因子：
29
通讯作者：
Cheng JX
中科院分区：
文献类型：
--
作者：
Yue S;Li J;Lee SY;Lee HJ;Shao T;Song B;Cheng L;Masterson TA;Liu X;Ratliff TL;Cheng JX
脂质代谢的改变越来越被认为是癌细胞的一个特征。通过无标记拉曼光谱显微镜，我们在单细胞水平上定量分析了人类患者癌组织的脂肪生成。我们的影像学数据显示，在高级别前列腺癌和转移性前列腺癌的脂滴中出现了意想不到的、异常的酯化胆固醇积累。生化研究表明，这种胆固醇酯积累是前列腺癌细胞中肿瘤抑制因子PTEN缺失和随后PI3K/AKT通路激活的结果。此外，我们发现这种积累是由外源脂蛋白的摄取显著增强和所需的胆固醇酯化引起的。在小鼠异种移植模型中，消耗胆固醇酯储存可显著降低肿瘤增殖，削弱癌症侵袭能力，抑制肿瘤生长，毒性可忽略不计。这些发现为通过改变胆固醇代谢来诊断和治疗前列腺癌提供了机会。
Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism.
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影响因子：
64.8
作者：
HABENICHT, AJR;SALBACH, P;GLOMSET, JA
通讯作者：
GLOMSET, JA
影响因子：
11.5
作者：
Kobayashi, Naoko;Barnard, R. James;Aronson, William J.
通讯作者：
Aronson, William J.
DOI：
10.1006/bbrc.1997.6799
发表时间：
1997-06-18
影响因子：
3.1
作者：
Ghosh, J;Myers, CE
通讯作者：
Myers, CE
影响因子：
3.8
作者：
Antalis, Caryl J.;Arnold, Tyler;Siddiqui, Rafat A.
通讯作者：
Siddiqui, Rafat A.
DOI：
10.1073/pnas.1534923100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Horton, JD;Shah, NA;Goldstein, JL
通讯作者：
Goldstein, JL