Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling
Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling
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DOI：
10.1074/jbc.m116.751263
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发表时间：
2016-11-11
影响因子：
4.8
通讯作者：
Itano, Naoki
中科院分区：
文献类型：
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作者：
Chanmee, Theerawut;Ontong, Pawared;Itano, Naoki
癌症干细胞（CSC）代表自我更新致癌细胞的一个小亚群。与许多其他干细胞一样，代谢重编程被认为是CSC的关键特征。然而，人们对癌细胞的代谢特征如何被控制以协调其CSC样特性知之甚少。我们最近证明，透明质酸（HA）的过度生产允许塑料癌细胞恢复到干细胞状态。在这里，我们采用稳定的同位素辅助示踪和质谱分析来阐明HA过量产生的乳腺癌细胞的代谢特征。这些综合方法公开了己糖胺生物合成途径（HBP）中代谢通量的加速。通过定量靶向代谢组学也可以明显看出代谢向糖酵解的转变，这一点通过关键糖酵解酶的表达谱得到了验证。谷氨酰胺：果糖-6-磷酸酰胺转移酶1（GFAT 1），HBP限速酶的强制表达，类似于HA过量生产的结果，就HIF-1的积累和糖酵解程序，而GFAT 1抑制显着降低HA过量生产的癌细胞中的HIF-1蛋白水平。此外，HBP-HIF-1轴的抑制废除了HA驱动的糖酵解增强，并减少了CSC样亚群。综上所述，我们的研究结果提供了令人信服的证据表明，HA的产生通过HBP偶联HIF-1信号调节乳腺癌细胞的代谢和CSC样特性。
Cancer stem cells (CSCs) represent a small subpopulation of self-renewing oncogenic cells. As in many other stem cells, metabolic reprogramming has been implicated to be a key characteristic of CSCs. However, little is known about how the metabolic features of cancer cells are controlled to orchestrate their CSC-like properties. We recently demonstrated that hyaluronan (HA) overproduction allowed plastic cancer cells to revert to stem cell states. Here, we adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells. These integrated approaches disclosed an acceleration of metabolic flux in the hexosamine biosynthetic pathway (HBP). A metabolic shift toward glycolysis was also evident by quantitative targeted metabolomics, which was validated by the expression profiles of key glycolytic enzymes. Forced expression of glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), an HBP rate-limiting enzyme, resembled the results of HA overproduction with regard to HIF-1 accumulation and glycolytic program, whereas GFAT1 inhibition significantly decreased HIF-1 protein level in HA-overproducing cancer cells. Moreover, inhibition of the HBP-HIF-1 axis abrogated HA-driven glycolytic enhancement and reduced the CSC-like subpopulation. Taken together, our results provide compelling evidence that HA production regulates the metabolic and CSC-like properties of breast cancer cells via HBP-coupled HIF-1 signaling.