Ketone bodies and two-compartment tumor metabolism Stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells
Ketone bodies and two-compartment tumor metabolism Stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells
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DOI：
10.4161/cc.22136
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发表时间：
2012-11-01
期刊：
影响因子：
4.3
通讯作者：
Sotgia, Federica
中科院分区：
文献类型：
--
作者：
Martinez-Outschoorn, Ubaldo E.;Lin, Zhao;Sotgia, Federica
我们之前已经提出酮体代谢对肿瘤的进展和转移至关重要。在这里，我们利用人类乳腺癌细胞（MCF7）和htert永生化成纤维细胞的共培养系统，为直接支持这一假设提供了新的证据。更具体地说，我们表明酮体生产所需的酶在癌症相关成纤维细胞中高度上调。这似乎是由间质表达的小窝蛋白-1 （Cav-1）和/或血清饥饿所控制的。此外，用酮体（如3-羟基丁酸酯和/或丁二醇）治疗足以驱动人类乳腺癌细胞中的线粒体生物发生。无偏蛋白质组学分析也证实了这一观察结果。有趣的是，MCT1抑制剂足以阻断人类乳腺癌细胞线粒体生物发生的发生，这为抗癌治疗提供了可能的途径。最后，利用人乳腺癌肿瘤样本，我们直接证实了与酮体生成相关的酶（HMGCS2、HMGCL和BDH1）在肿瘤基质中优先表达。相反，与酮类再利用相关的酶（ACAT1）和线粒体生物发生相关的酶（HSP60）与上皮肿瘤细胞室选择性相关。我们目前的发现与“双室肿瘤代谢”模型是一致的。此外，他们建议我们应该将酮体代谢作为一个新的药物发现领域，用于预防和治疗人类癌症。
We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the "two-compartment tumor metabolism" model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers.