College of Pharmacy, Sookmyung Women's University, Seoul, 04312, South Korea.
Environmental Risk and Welfare Research Team, Korea Basic Science Institute, Seoul, 02841, South Korea.
Biochem Biophys Res Commun. 2019 Oct 29;519(1):100-105. doi: 10.1016/j.bbrc.2019.08.137. Epub 2019 Aug 31.
Lipid metabolism is associated with colon cancer prognosis and incidence. Stearoyl-CoA desaturase 1 (SCD1), which converts fully saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), has been suggested as a vulnerable target for selective elimination of cancer stem cells (CSCs). However, the clinical significance and physiological role of SCD1 in CSCs has not been well demonstrated. Here, we showed the clinical and biochemical relevance of blocking SCD1 to target CSCs by analyzing human colon cancer data from TCGA and through lipidomic profiling of CSCs with or without SCD1 inhibition using mass spectrometry. Positive associations between SCD1 expression and colorectal cancer patient clinical status and the expression of CSC-related genes (WNT and NOTCH signaling) were found based on TCGA data analysis. Lipidomic profiling of CSCs and bulk cancer cells (BCCs) using mass spectrometry revealed that colon CSCs contained a distinctive lipid profile, with higher free MUFA and lower free SFA levels than in BCCs, suggesting that enhanced SCD1 activity generates MUFAs that may support WNT signaling in CSCs. In addition, all identified phosphatidyl-ethanolamine-containing MUFAs were found at higher levels in CSCs. Interestingly, we observed lower phosphatidyl-serine (18:1/18:0), phosphatidyl-choline (PC; p-18:0/18:1)), and sphingomyelin (SM; d18:1/20:0 or d16:1/22:0) levels in CSCs than in BCCs. Of those, SCD1 inhibition, which efficiently diminished free MUFA levels, increased those specific PC and SM and MUFAs in CSCs promptly. These results suggest that these specific lipid composition is critical for CSC stem cell maintenance. In addition, not only free MUFAs, which are known to be required for WNT signaling, but also other phospholipids, such as SM, which are important for lipid raft formation, may mediate other cell signaling pathways that support CSC maintenance. Comparison of the lipidomic profiles of colon cancer cells with those of previously reported for glioma cells further demonstrated the tissue specific characteristics of lipid metabolism in CSCs.
脂代谢与结肠癌的预后和发生有关。硬脂酰辅酶 A 去饱和酶 1（SCD1）可将完全饱和脂肪酸（SFAs）转化为单不饱和脂肪酸（MUFAs），被认为是选择性消除癌症干细胞（CSC）的脆弱靶点。然而，SCD1 在 CSC 中的临床意义和生理作用尚未得到很好的证明。在这里，我们通过分析 TCGA 中的人类结肠癌数据，并通过使用质谱法对 SCD1 抑制的 CSC 进行脂质组学分析，显示了阻断 SCD1 以靶向 CSC 的临床和生化相关性。基于 TCGA 数据分析，发现 SCD1 表达与结直肠癌患者临床状况以及 CSC 相关基因（WNT 和 NOTCH 信号）的表达之间存在正相关。使用质谱法对 CSC 和大量癌细胞（BCC）进行脂质组学分析显示，结肠 CSC 具有独特的脂质谱，其游离 MUFA 水平高于 BCC，游离 SFA 水平低于 BCC，这表明增强的 SCD1 活性产生的 MUFAs 可能支持 CSC 中的 WNT 信号。此外，在 CSC 中发现所有鉴定出的含有磷酯酰乙醇胺的 MUFA 水平都更高。有趣的是，我们观察到 CSC 中的磷脂酰丝氨酸（18:1/18:0）、磷脂酰胆碱（PC；p-18:0/18:1）和鞘磷脂（SM；d18:1/20:0 或 d16:1/22:0）水平低于 BCC。其中，SCD1 抑制有效地降低了游离 MUFA 水平，迅速增加了 CSC 中这些特定的 PC 和 SM 和 MUFA。这些结果表明，这种特定的脂质组成对于 CSC 干细胞的维持至关重要。此外，不仅是已知对 WNT 信号必需的游离 MUFAs，而且还有其他磷脂，例如对于脂质筏形成很重要的 SM，可能介导支持 CSC 维持的其他细胞信号通路。与先前报道的神经胶质瘤细胞的脂质组学图谱进行比较，进一步证明了 CSC 中脂代谢的组织特异性特征。
