Zhang Le, Ramesh Prashanthi, Atencia Taboada Lidia, Roessler Rebecca, Zijlmans Dick W, Vermeulen Michiel, Picavet-Havik Daisy I, van der Wel Nicole N, Vaz Frédéric M, Medema Jan Paul
LEXOR, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Oncode Institute, Amsterdam, The Netherlands.
Cell Death Differ. 2025 Apr;32(4):657-671. doi: 10.1038/s41418-024-01418-y. Epub 2024 Nov 23.
Elevated de novo lipid synthesis is a remarkable adaptation of cancer cells that can be exploited for therapy. However, the role of altered lipid metabolism in the regulation of apoptosis is still poorly understood. Using thermal proteome profiling, we identified Manidipine-2HCl, targeting UGT8, a key enzyme in the synthesis of sulfatides. In agreement, lipidomic analysis indicated that sulfatides are strongly reduced in colorectal cancer cells upon treatment with Manidipine-2HCl. Intriguingly, this reduction led to severe mitochondrial swelling and a strong synergism with BH3 mimetics targeting BCL-XL, leading to the activation of mitochondria-dependent apoptosis. Mechanistically, Manidipine-2HCl enhanced mitochondrial BAX localization in a sulfatide-dependent fashion, facilitating its activation by BH3 mimetics. In conclusion, our data indicates that UGT8 mediated synthesis of sulfatides controls mitochondrial homeostasis and BAX localization, dictating apoptosis sensitivity of colorectal cancer cells.
从头脂质合成增加是癌细胞的一种显著适应性变化，可用于治疗。然而，脂质代谢改变在细胞凋亡调控中的作用仍知之甚少。我们利用热蛋白质组分析，鉴定出盐酸马尼地平靶向UGT8，UGT8是硫苷脂合成中的关键酶。与此一致，脂质组分析表明，用盐酸马尼地平处理后，结肠直肠癌细胞中的硫苷脂显著减少。有趣的是，这种减少导致严重的线粒体肿胀，并与靶向BCL-XL的BH3模拟物产生强烈协同作用，从而导致线粒体依赖性细胞凋亡的激活。从机制上讲，盐酸马尼地平以硫苷脂依赖性方式增强线粒体BAX定位，促进其被BH3模拟物激活。总之，我们的数据表明，UGT8介导的硫苷脂合成控制线粒体稳态和BAX定位，决定结肠直肠癌细胞的凋亡敏感性。
