Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells.
Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells.
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DOI：
10.18632/oncotarget.4401
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发表时间：
2015-06-20
期刊：
影响因子：
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通讯作者：
Sotgia F
中科院分区：
文献类型：
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作者：
De Luca A;Fiorillo M;Peiris-Pagès M;Ozsvari B;Smith DL;Sanchez-Alvarez R;Martinez-Outschoorn UE;Cappello AR;Pezzi V;Lisanti MP;Sotgia F
在这里，我们表明，新的线粒体生物合成所需的锚定独立的生存和癌症干细胞样细胞（CSC）的繁殖。更具体地说，我们使用药物XCT 790作为研究工具，因为它是ERRα-PGC 1信号通路的特异性抑制剂，该通路控制线粒体生物发生。有趣的是，我们的结果直接证明，XCT 790有效地阻断肿瘤起始干细胞样细胞（TIC）的存活和增殖，使用MCF 7细胞系作为模型系统。从机制上讲，我们表明XCT 790抑制了CSC存活通常所需的几种独立信号通路的活性，如Sonic hedgehog、TGFβ-SMAD、STAT 3和Wnt信号通路。我们还表明，XCT 790显着降低氧化线粒体代谢（OXPHOS）和XCT 790介导的抑制CSC的繁殖可以防止或逆转乙酰-L-肉毒碱（ALCAR），线粒体燃料。与我们的研究结果一致，ERRα的过表达显著增强了乳腺球形成的效率，这可以通过线粒体抑制剂治疗来阻断。类似地，由F0 XM 1（Wnt/β-连环蛋白信号传导的下游靶标）增强的乳腺球形成也可以通过用三种不同类型的线粒体抑制剂（XCT 790、寡霉素A或多西环素）处理来阻断。在这种情况下，我们的无偏蛋白质组学分析表明，FOXM 1驱动与MCF 7细胞中的线粒体生物发生、糖酵解、EMT和蛋白质合成相关的>90种蛋白质靶标的表达，这些过程是合成代谢CSC表型的特征。最后，强力霉素是FDA批准的抗生素，患者耐受性良好。因此，多西环素可以在临床上被重新利用为“安全”的线粒体抑制剂，以靶向CSC中的F0 XM 1和线粒体生物发生，以防止肿瘤复发和远处转移，从而避免患者复发。
Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERRα significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/β-catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (XCT790, oligomycin A, or doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90 protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally, doxycycline is an FDA-approved antibiotic, which is very well-tolerated in patients. As such, doxycycline could be re-purposed clinically as a ‘safe’ mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent tumor recurrence and distant metastasis, thereby avoiding patient relapse.