Hypoxia induced deregulation of sphingolipids in colon cancer is a prognostic marker for patient outcome

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-01, Vol.1870 (1), p.166906-166906, Article 166906
• Main Authors: El Hindi, Khadija, Brachtendorf, Sebastian, Hartel, Jennifer C., Renné, Christoph, Birod, Kerstin, Schilling, Karin, Labocha, Sandra, Thomas, Dominique, Ferreirós, Nerea, Hahnefeld, Lisa, Dorochow, Erika, Del Turco, Domenico, Deller, Thomas, Scholich, Klaus, Fuhrmann, Dominik C., Weigert, Andreas, Brüne, Bernhard, Geisslinger, Gerd, Wittig, Ilka, Link, Karl-Heinrich, Grösch, Sabine
• Format: Article
• Language: English
• Subjects: Biomarker; Lipidomic; Metabolism; Oxidative consumption rate, hypoxia; Proteomic
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2023.166906

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). [Display omitted] •CerS4 and CerS5 are downregulated in colon cancer by hypoxic stress•Downregulation of CerS4 and CerS5 in aggressive growing colon cancer cell lines enhances tumor growth in vitro and in vivo•CerS4 downregulation in HCT-116 promotes tumor growth by metabolic changes to the Warburg effect•CerS5 downregulation in HCT-116 promotes tumor growth by upregulation of oncogenes•Late stage colon tumors with low CerS4 and CerS5 expression level predict a worse patient out come