The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells.
The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells.
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DOI：
10.18632/oncoscience.314
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Lupu R
中科院分区：
文献类型：
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作者：
Menendez JA;Vellon L;Espinoza I;Lupu R
血管生成诱导剂CCN 1（富含半胱氨酸61，CYR 61）在转移性乳腺癌中被差异激活。然而，关于CCN 1的促转移作用的确切机制知之甚少。在这里，我们研究了CCN 1表达对脂肪酸合成酶（FATCH）的影响，FATCH是一种代谢癌基因，被认为为癌细胞提供增殖和存活优势。在MCF-7细胞中强制表达CCN 1可显著上调FXR蛋白表达，并显著增加FXR基因启动子活性2- 3倍，而FXR启动子中固醇反应元件结合蛋白（SREBP）结合位点的缺失可完全消除CCN 1驱动的转录激活。MAPK或PI-3 ′ K活化的药理学阻断类似地阻止了CCN 1诱导FXR基因活化的能力。真菌毒素浅蓝菌素或小分子化合物C75对Festival活性的药理学抑制逆转了CCN 1诱导的雌激素非依赖性获得和对激素治疗（如他莫昔芬和氟维司群）的耐药性（在锚定非依赖性生长试验中）。这项研究揭示了Fas依赖的内源性脂肪生成作为一种新的机制，控制转移表型促进CCN 1。由于雌激素不依赖性和进展为转移性表型是乳腺癌治疗耐药性和死亡率的标志，这种以前未被认识到的CCN 1驱动的脂肪生成表型代表了临床管理转移性疾病进展的新代谢靶点。
The angiogenic inducer CCN1 (Cysteine-rich 61, CYR61) is differentially activated in metastatic breast carcinomas. However, little is known about the precise mechanisms that underlie the pro-metastatic actions of CCN1. Here, we investigated the impact of CCN1 expression on fatty acid synthase (FASN), a metabolic oncogene thought to provide cancer cells with proliferative and survival advantages. Forced expression of CCN1 in MCF-7 cells robustly up-regulated FASN protein expression and also significantly increased FASN gene promoter activity 2- to 3-fold, whereas deletion of the sterol response element-binding protein (SREBP) binding site in the FASN promoter completely abrogated CCN1-driven transcriptional activation. Pharmacological blockade of MAPK or PI-3'K activation similarly prevented the ability of CCN1 to induce FASN gene activation. Pharmacological inhibition of FASN activity with the mycotoxin cerulenin or the small compound C75 reversed CCN1-induced acquisition of estrogen independence and resistance to hormone therapies such as tamoxifen and fulvestrant in anchorage-independent growth assays. This study uncovers FASNdependent endogenous lipogenesis as a new mechanism controlling the metastatic phenotype promoted by CCN1. Because estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer, this previously unrecognized CCN1-driven lipogenic phenotype represents a novel metabolic target to clinically manage metastatic disease progression.