Goethe-University Frankfurt, Institute of Clinical Pharmacology, Faculty of Medicine, Theodor Stern Kai 7, 60590 Frankfurt, Germany.
Goethe-University Frankfurt, Institute of Clinical Pharmacology, Faculty of Medicine, Theodor Stern Kai 7, 60590 Frankfurt, Germany; Goethe-University Frankfurt, Department of Life Sciences, 60590 Frankfurt, Germany.
Biochim Biophys Acta Mol Basis Dis. 2024 Jan;1870(1):166906. doi: 10.1016/j.bbadis.2023.166906. Epub 2023 Oct 4.
Sphingolipids are important for the physicochemical properties of cellular membranes and deregulated in tumors. In human colon cancer tissue ceramide synthase (CerS) 4 and CerS5 are reduced which correlates with a reduced survival probability of late-stage colon cancer patients. Both enzymes are reduced after hypoxia in advanced colorectal cancer (CRC) cells (HCT-116, SW620) but not in non-metastatic CRC cells (SW480, Caco-2). Downregulation of CerS4 or CerS5 in advanced CRC cells enhanced tumor formation in nude mice and organoid growth in vitro. This was accompanied by an enhanced proliferation rate and metabolic changes leading to a shift towards the Warburg effect. In contrast, CerS4 or CerS5 depletion in Caco-2 cells reduced tumor growth in vivo. Lipidomic and proteomic analysis of membrane fractions revealed significant changes in tumor-promoting cellular pathways and cellular transporters. This study identifies CerS4 and CerS5 as prognostic markers for advanced colon cancer patients and provides a comprehensive overview about the associated cellular metabolic changes. We propose that the expression level of CerS4 and CerS5 in colon tumors could serve as a basis for decision-making for personalized treatment of advanced colon cancer patients. Trial registration: The study was accredited by the study board of the Deutsche Krebsgesellschaft (Registration No: St-D203, 2017/06/30, retrospectively registered).
鞘脂是细胞膜物理化学性质的重要组成部分，在肿瘤中失调。在人类结肠癌组织中，神经酰胺合酶（CerS）4 和 CerS5 减少，这与晚期结肠癌患者的生存概率降低相关。在晚期结直肠癌细胞（HCT-116、SW620）缺氧后，这两种酶都会减少，但在非转移性结直肠癌细胞（SW480、Caco-2）中则不会。在晚期 CRC 细胞中下调 CerS4 或 CerS5 会增强裸鼠肿瘤形成和体外类器官生长。这伴随着增殖率的提高和代谢变化，导致向瓦博格效应转变。相比之下，在 Caco-2 细胞中耗尽 CerS4 或 CerS5 会减少体内肿瘤生长。膜部分的脂质组学和蛋白质组学分析显示，促进肿瘤的细胞途径和细胞转运蛋白发生了显著变化。本研究将 CerS4 和 CerS5 鉴定为晚期结肠癌患者的预后标志物，并全面概述了相关的细胞代谢变化。我们提出，结肠肿瘤中 CerS4 和 CerS5 的表达水平可以作为晚期结肠癌患者个体化治疗决策的基础。试验注册：该研究已获得德国癌症协会研究委员会的认可（注册号：St-D203，2017 年 6 月 30 日，回溯注册）。
