Background Humans produce heat through non-shivering thermogenesis, a metabolic process that occurs in inducible beige adipocytes expressing uncoupling protein 1 (UCP1). UCP1 dissipates the proton gradient of the mitochondrial inner membrane and converts that energy into heat. It is unclear whether cancer cells can exhibit autonomous thermogenesis. Previously, we found that the knockdown of hypoxia-inducible fatty acid binding protein 7 (FABP7) increased reactive oxygen species (ROS) in breast cancer cells. ROS are known to induce beige adipocyte differentiation. Methods We investigated the association of tumor hypoxia, FABP7, and UCP1 across breast cancer patients using METABRIC and TCGA data sets. Furthermore, using a breast cancer cell line, HCC1806, we tested the effect of FABP7 knockdown on cellular physiology including thermogenesis. Results We found a strong mutual exclusivity of FABP7 and UCP1 expression both in METABRIC and in TCGA, indicating major metabolic phenotypic differences. FABP7 was preferentially distributed in poorly differentiated-, estrogen receptor (ER) negative tumors. In contrast, UCP1 was highly expressed in normal ducts and well-differentiated-, ER positive-, less hypoxic tumors. In the cell line-based experiments, UCP1 and its transcriptional regulators were upregulated upon FABP7 knockdown. UCP1 was induced in about 20% of cancer cells, and the effect was increased further in hypoxia. UCP1 depolarized mitochondrial membranes at the site of expression. UCP1 induction was associated with the increase in proton leak, glycolysis, and maximal respiration, mimicking the typical energy profile of beige adipocytes. Most importantly, UCP1 induction elevated cancer cell temperature associated with increased vulnerability to hypoxia and γ-irradiation. Conclusions We demonstrated that breast cancer cells can undergo thermogenesis through UCP1 induction. Disrupting FABP7-mediated fatty acid metabolism can unlock UCP1-mediated thermogenesis, potentially making it possible to develop therapies to target thermogenesis. Further study would be warranted to investigate the effect of rise in temperature of cancer cells on patients’ outcomes and the relationship to other metabolic pathways.

中文翻译：

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缺氧诱导脂肪酸结合蛋白7的破坏诱导乳腺癌细胞米色脂肪样分化和生热作用


背景人类通过非颤抖产热产生热量，这是一种发生在表达解偶联蛋白 1 (UCP1) 的诱导米色脂肪细胞中的代谢过程。 UCP1 消散线粒体内膜的质子梯度并将能量转化为热量。目前尚不清楚癌细胞是否能够表现出自主生热作用。此前，我们发现缺氧诱导脂肪酸结合蛋白7（FABP7）的敲低会增加乳腺癌细胞中的活性氧（ROS）。众所周知，ROS 可以诱导米色脂肪细胞分化。方法 我们使用 METABRIC 和 TCGA 数据集研究了乳腺癌患者中肿瘤缺氧、FABP7 和 UCP1 的关联。此外，我们使用乳腺癌细胞系 HCC1806 测试了 FABP7 敲低对细胞生理学（包括生热作用）的影响。结果我们发现 METABRIC 和 TCGA 中 FABP7 和 UCP1 表达具有很强的相互排斥性，表明主要的代谢表型差异。 FABP7 优先分布于低分化、雌激素受体 (ER) 阴性肿瘤中。相反，UCP1在正常导管和分化良好、ER阳性、缺氧程度较低的肿瘤中高表达。在基于细胞系的实验中，UCP1 及其转录调节因子在 FABP7 敲低后上调。 UCP1在大约20%的癌细胞中被诱导，并且在缺氧时效果进一步增强。 UCP1 使表达位点的线粒体膜去极化。 UCP1 诱导与质子泄漏、糖酵解和最大呼吸的增加相关，模仿米色脂肪细胞的典型能量分布。最重要的是，UCP1 诱导会升高癌细胞温度，从而增加对缺氧和 γ 辐射的脆弱性。 结论 我们证明乳腺癌细胞可以通过 UCP1 诱导进行生热作用。破坏 FABP7 介导的脂肪酸代谢可以解锁 UCP1 介导的产热作用，从而有可能开发针对产热作用的疗法。需要进一步的研究来调查癌细胞温度升高对患者预后的影响以及与其他代谢途径的关系。