De Luca Arianna, Fiorillo Marco, Peiris-Pagès Maria, Ozsvari Bela, Smith Duncan L, Sanchez-Alvarez Rosa, Martinez-Outschoorn Ubaldo E, Cappello Anna Rita, Pezzi Vincenzo, Lisanti Michael P, Sotgia Federica
The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.
The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.
Oncotarget. 2015 Jun 20;6(17):14777-95. doi: 10.18632/oncotarget.4401.
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.
在此，我们表明新的线粒体生物合成对于癌症干细胞样细胞（CSCs）的锚定非依赖性存活和增殖是必需的。更具体地说，我们使用药物XCT790作为研究工具，因为它作为ERRα - PGC1信号通路的特异性抑制剂发挥作用，该信号通路控制线粒体生物合成。有趣的是，我们的结果直接证明，以MCF7细胞系作为模型系统，XCT790有效地阻断了肿瘤起始干细胞样细胞（TICs）的存活和增殖。从机制上讲，我们表明XCT790抑制了几种独立的信号通路的活性，这些信号通路通常是CSCs存活所必需的，如音猬因子、TGFβ - SMAD、STAT3和Wnt信号通路。我们还表明XCT790显著降低氧化线粒体代谢（OXPHOS），并且XCT790介导的CSC增殖抑制可被线粒体燃料乙酰 - L - 肉碱（ALCAR）预防或逆转。与我们的发现一致，ERRα的过表达显著提高了乳腺球形成的效率，这可以通过用线粒体抑制剂处理来阻断。同样，由Wnt/β - 连环蛋白信号通路的下游靶点FOXM1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（XCT790、寡霉素A或强力霉素）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，FOXM1驱动了与MCF7细胞中线粒体生物合成、糖酵解、上皮间质转化和蛋白质合成相关的90多个蛋白质靶点的表达，这些过程是合成代谢CSC表型的特征。最后，强力霉素是一种FDA批准的抗生素，患者对其耐受性良好。因此，强力霉素可以在临床上重新用作“安全”的线粒体抑制剂，以靶向CSCs中的FOXM1和线粒体生物合成，预防肿瘤复发和远处转移，从而避免患者复发。
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