Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo
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...
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2021-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/19/10539 |
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| author | Richard Jennemann Martina Volz Felix Bestvater Claudia Schmidt Karsten Richter Sylvia Kaden Johannes Müthing Hermann-Josef Gröne Roger Sandhoff |
| author_facet | Richard Jennemann Martina Volz Felix Bestvater Claudia Schmidt Karsten Richter Sylvia Kaden Johannes Müthing Hermann-Josef Gröne Roger Sandhoff |
| author_sort | Richard Jennemann |
| collection | DOAJ |
| description | 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- (<i>UGCG</i>). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. <i>UGCG</i> 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. |
| first_indexed | 2024-03-10T07:00:20Z |
| format | Article |
| id | doaj.art-e51e86b8869d4369aa31a8c5b43f6613 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:00:20Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e51e86b8869d4369aa31a8c5b43f66132023-11-22T16:11:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-0122191053910.3390/ijms221910539Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In VivoRichard Jennemann0Martina Volz1Felix Bestvater2Claudia Schmidt3Karsten Richter4Sylvia Kaden5Johannes Müthing6Hermann-Josef Gröne7Roger Sandhoff8Lipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, GermanyLipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, GermanyLight Microscopy Facility, German Cancer Research Center, 69120 Heidelberg, GermanyLight Microscopy Facility, German Cancer Research Center, 69120 Heidelberg, GermanyCore Facility Electron Microscopy, German Cancer Research Center, 69120 Heidelberg, GermanyCore Facility Electron Microscopy, German Cancer Research Center, 69120 Heidelberg, GermanyInstitute for Hygiene, University of Münster, 48149 Münster, GermanyMedical Faculty, University of Heidelberg, 69120 Heidelberg, GermanyLipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, GermanyColorectal 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- (<i>UGCG</i>). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. <i>UGCG</i> 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.https://www.mdpi.com/1422-0067/22/19/10539glucosylceramide synthaseglycosphingolipidsazoxymethanedextrane sulfatecolorectal cancercationic amphiphilic drugs |
| spellingShingle | Richard Jennemann Martina Volz Felix Bestvater Claudia Schmidt Karsten Richter Sylvia Kaden Johannes Müthing Hermann-Josef Gröne Roger Sandhoff Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo International Journal of Molecular Sciences glucosylceramide synthase glycosphingolipids azoxymethane dextrane sulfate colorectal cancer cationic amphiphilic drugs |
| title | Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo |
| title_full | Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo |
| title_fullStr | Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo |
| title_full_unstemmed | Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo |
| title_short | Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo |
| title_sort | blockade of glycosphingolipid synthesis inhibits cell cycle and spheroid growth of colon cancer cells in vitro and experimental colon cancer incidence in vivo |
| topic | glucosylceramide synthase glycosphingolipids azoxymethane dextrane sulfate colorectal cancer cationic amphiphilic drugs |
| url | https://www.mdpi.com/1422-0067/22/19/10539 |
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