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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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.

Details

Title
Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo
Author
Jennemann, Richard 1   VIAFID ORCID Logo  ; Volz, Martina 1 ; Bestvater, Felix 2 ; Schmidt, Claudia 2 ; Richter, Karsten 3   VIAFID ORCID Logo  ; Kaden, Sylvia 3 ; Müthing, Johannes 4   VIAFID ORCID Logo  ; Hermann-Josef Gröne 5 ; Sandhoff, Roger 1   VIAFID ORCID Logo 

 Lipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, Germany; [email protected] (M.V.); [email protected] (R.S.) 
 Light Microscopy Facility, German Cancer Research Center, 69120 Heidelberg, Germany; [email protected] (F.B.); [email protected] (C.S.) 
 Core Facility Electron Microscopy, German Cancer Research Center, 69120 Heidelberg, Germany; [email protected] (K.R.); [email protected] (S.K.) 
 Institute for Hygiene, University of Münster, 48149 Münster, Germany; [email protected] 
 Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany; [email protected]; Institute of Pharmacology, University of Marburg, 35043 Marburg, Germany 
First page
10539
Publication year
2021
Publication date
2021
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2581020143
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.