A Proof-of-Concept Inhibitor of Endothelial Lipase Suppresses Triple-Negative Breast Cancer Cells by Hijacking the Mitochondrial Function.
A Proof-of-Concept Inhibitor of Endothelial Lipase Suppresses Triple-Negative Breast Cancer Cells by Hijacking the Mitochondrial Function.
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一种概念验证的内皮脂肪酶抑制剂通过劫持线粒体功能来抑制三阴性乳腺癌细胞
DOI：
10.3390/cancers14153763
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发表时间：
2022-08-02
期刊：
影响因子：
5.2
通讯作者：
Zhou, Qun
中科院分区：
文献类型：
--
作者：
Yang, Rongze;Han, Shuyan;Clayton, Joseph;Haghighatian, Mahan;Tsai, Cheng-Chieh;Yao, Yuan;Li, Pingping;Shen, Jana;Zhou, Qun
关键词：
内皮脂酶（EL/LIPG）是肿瘤细胞代谢的关键调节因子。在三阴性乳腺癌（TNBC）细胞中，我们发现LIPG的表达与长非编码RNA DANCR相关，并且与线粒体代谢-氧化磷酸化（OXPHOS）的基因特征正相关。DANCR与LIPG结合，使肿瘤细胞能够维持其表达。重要的是，LIPG敲低抑制OXPHOS和TNBC肿瘤形成。最后，我们的研究确定了一种天然化合物，LIPG抑制剂cynaroside，这为TNBC提供了一种新的治疗策略。三阴性乳腺癌（TNBC）细胞重新编程其代谢，为肿瘤细胞在肿瘤微环境中的生长和存活提供代谢灵活性。虽然我们以前的研究结果表明，内皮脂肪酶（EL/LIPG）是TNBC的标志，但LIPG引发TNBC代谢的确切机制仍不明确。在这里，我们报告说，LIPG的表达与长的非编码RNA DANCR和正相关的线粒体代谢氧化磷酸化（OXPHOS）的基因签名。DANCR与LIPG结合，使肿瘤细胞能够维持LIPG蛋白的稳定性和OXPHOS。作为LIPG调节肿瘤细胞氧化代谢的机制之一，LIPG介导组蛋白去乙酰化酶6（HDAC 6）和组蛋白乙酰化，从而导致IL-6和脂肪酸合成基因表达的改变。最后，在宽松对接方法的帮助下，我们发现了一种新的LIPG抑制剂，cynaroside，它有效地抑制了TNBC细胞中的酶活性和DANCR。用洋蓟苷处理抑制了TNBC细胞的OXPHOS表型，这严重损害了肿瘤形成。总之，我们的研究提供了对TNBC中线粒体代谢的LIPG调节的机制性见解，并证明了靶向LIPG是治疗TNBC的有前途的新治疗策略的概念。
Endothelial lipase (EL/LIPG) is a key regulator of tumor cell metabolism. In triple-negative breast cancer (TNBC) cells, we find that the expression of LIPG is associated with long non-coding RNA DANCR and positively correlates with gene signatures of mitochondrial metabolism-oxidative phosphorylation (OXPHOS). DANCR binds to LIPG, which enables tumor cells to maintain the expression. Importantly, LIPG knockdown inhibits OXPHOS and TNBC tumor formation. Finally, our study identifies a natural compound, the LIPG inhibitor cynaroside, which provides a new therapeutic strategy against TNBC. Triple-negative breast cancer (TNBC) cells reprogram their metabolism to provide metabolic flexibility for tumor cell growth and survival in the tumor microenvironment. While our previous findings indicated that endothelial lipase (EL/LIPG) is a hallmark of TNBC, the precise mechanism through which LIPG instigates TNBC metabolism remains undefined. Here, we report that the expression of LIPG is associated with long non-coding RNA DANCR and positively correlates with gene signatures of mitochondrial metabolism-oxidative phosphorylation (OXPHOS). DANCR binds to LIPG, enabling tumor cells to maintain LIPG protein stability and OXPHOS. As one mechanism of LIPG in the regulation of tumor cell oxidative metabolism, LIPG mediates histone deacetylase 6 (HDAC6) and histone acetylation, which contribute to changes in IL-6 and fatty acid synthesis gene expression. Finally, aided by a relaxed docking approach, we discovered a new LIPG inhibitor, cynaroside, that effectively suppressed the enzyme activity and DANCR in TNBC cells. Treatment with cynaroside inhibited the OXPHOS phenotype of TNBC cells, which severely impaired tumor formation. Taken together, our study provides mechanistic insights into the LIPG modulation of mitochondrial metabolism in TNBC and a proof-of-concept that targeting LIPG is a promising new therapeutic strategy for the treatment of TNBC.
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影响因子：
7.7
作者：
Lo PK;Yao Y;Lee JS;Zhang Y;Huang W;Kane MA;Zhou Q
通讯作者：
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影响因子：
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作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
4.4
作者：
Hirano T
通讯作者：
Hirano T
影响因子：
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作者：
Giró-Perafita A;Sarrats A;Pérez-Bueno F;Oliveras G;Buxó M;Brunet J;Viñas G;Miquel TP
通讯作者：
Miquel TP
影响因子：
5.7
作者：
Kuemmerle NB;Rysman E;Lombardo PS;Flanagan AJ;Lipe BC;Wells WA;Pettus JR;Froehlich HM;Memoli VA;Morganelli PM;Swinnen JV;Timmerman LA;Chaychi L;Fricano CJ;Eisenberg BL;Coleman WB;Kinlaw WB
通讯作者：
Kinlaw WB