Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo
| Autor: | Claudia Schmidt, Sylvia Kaden, Karsten Richter, Roger Sandhoff, Richard Jennemann, Felix Bestvater, Hermann-Josef Gröne, Martina Volz, Johannes Müthing |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
glucosylceramide synthase
Pyrrolidines Colorectal cancer QH301-705.5 medicine.medical_treatment colorectal cancer Catalysis Article Inorganic Chemistry Dioxanes chemistry.chemical_compound Mice In vivo Spheroids Cellular medicine Gene silencing Animals Humans Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy cationic amphiphilic drugs Chemotherapy dextrane sulfate glycosphingolipids Azoxymethane Organic Chemistry Cell Cycle General Medicine Glycosphingolipid Neoplasms Experimental Cell cycle medicine.disease HCT116 Cells In vitro Computer Science Applications Neoplasm Proteins Chemistry chemistry azoxymethane Glucosyltransferases Colonic Neoplasms Cancer research |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 19 International Journal of Molecular Sciences, Vol 22, Iss 10539, p 10539 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms221910539 |
| Popis: | Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in humans. At early stages CRC is treated by surgery and at advanced stages combined with chemotherapy. We examined here the potential effect of glucosylceramide synthase (GCS)-inhibition on CRC biology. GCS is the rate-limiting enzyme in the glycosphingolipid (GSL)-biosynthesis pathway and overexpressed in many human tumors. We suppressed GSL-biosynthesis using the GCS inhibitor Genz-123346 (Genz), NB-DNJ (Miglustat) or by genetic targeting of the GCS-encoding gene UDP-glucose-ceramide-glucosyltransferase- (UGCG). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. UGCG silencing strongly also inhibited tumor spheroid growth in Lovo cells and moderately in HCT116 cells. MS/MS analysis demonstrated markedly elevated levels of sphingomyelin (SM) and phosphatidylcholine (PC) that occurred in a Genz-concentration dependent manner. Ultrastructural analysis of Genz-treated cells indicated multi-lamellar lipid storage in vesicular compartments. In mice, Genz lowered the incidence of experimentally induced colorectal tumors and in particular the growth of colorectal adenomas. These results highlight the potential for GCS-based inhibition in the treatment of CRC. |
| Databáze: | OpenAIRE |
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