Kawashima Masahiro, Bensaad Karim, Zois Christos E, Barberis Alessandro, Bridges Esther, Wigfield Simon, Lagerholm Christoffer, Dmitriev Ruslan I, Tokiwa Mariko, Toi Masakazu, Papkovsky Dmitri B, Buffa Francesca M, Harris Adrian L
Department of Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS UK.
Department of Breast Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606 8507 Japan.
Cancer Metab. 2020 Jul 6;8:13. doi: 10.1186/s40170-020-00219-4. eCollection 2020.
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.
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.
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.
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.
人类通过非寒战性产热来产生热量，这是一种发生在表达解偶联蛋白1（UCP1）的可诱导米色脂肪细胞中的代谢过程。UCP1消除线粒体内膜的质子梯度，并将该能量转化为热量。目前尚不清楚癌细胞是否能表现出自主产热。此前，我们发现缺氧诱导型脂肪酸结合蛋白7（FABP7）的敲低会增加乳腺癌细胞中的活性氧（ROS）。已知ROS可诱导米色脂肪细胞分化。
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之间的关联。此外，我们使用乳腺癌细胞系HCC1806，测试了FABP7敲低对包括产热在内的细胞生理学的影响。
我们发现在METABRIC和TCGA中，FABP7和UCP1的表达存在强烈的相互排斥性，表明存在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在正常导管以及高分化、ER阳性、低缺氧肿瘤中高表达。在基于细胞系的实验中，FABP7敲低后UCP1及其转录调节因子上调。约20%的癌细胞中诱导出UCP1，在缺氧条件下这种效应进一步增强。UCP1在表达部位使线粒体膜去极化。UCP1的诱导与质子泄漏、糖酵解和最大呼吸的增加相关，模拟了米色脂肪细胞的典型能量特征。最重要的是，UCP1的诱导提高了癌细胞温度，同时增加了对缺氧和γ射线照射的易感性。
我们证明乳腺癌细胞可通过UCP1的诱导进行产热。破坏FABP7介导的脂肪酸代谢可开启UCP1介导的产热，这可能使开发针对产热的治疗方法成为可能。有必要进一步研究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。
