S1P lyase regulates intestinal stem cell quiescence via Ki-67 and FOXO3

  • Background: Reduction of the Sphingosine-1-phosphate (S1P) degrading enzyme S1P lyase 1 (SGPL1) initiates colorectal cancer progression with parallel loss of colon function in mice. We aimed to investigate the effect of SGPL1 knockout on the stem cell niche in these mice. Methods: We performed immunohistochemical and multi-fluorescence imaging on tissue sections of wildtype and SGPL1 knockout colons under disease conditions. Furthermore, we generated SGPL1 knockout DLD-1 cells (SGPL1−/−M.Ex1) using CRISPR/Cas9 and characterized cell cycle and AKT signaling pathway via Western blot, immunofluorescence, and FACS analysis. Results: SGPL1 knockout mice were absent of anti-Ki-67 staining in the stem cell niche under disease conditions. This was accompanied by an increase of the negative cell cycle regulator FOXO3 and attenuation of CDK2 activity. SGPL1−/−M.Ex1 cells show a similar FOXO3 increase but no arrest of proliferation, although we found a suppression of the PDK1/AKT signaling pathway, a prolonged G1-phase, and reduced stem cell markers. Conclusions: While already established colon cancer cells find escape mechanisms from cell cycle arrest, in vivo SGPL1 knockout in the colon stem cell niche during progression of colorectal cancer can contribute to cell cycle quiescence. Thus, we propose a new function of the S1P lyase 1 in stemness.

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Author:Anja SchwiebsORCiDGND, W. Farha Faqar-Uz-ZamanGND, Martina Herrero San Juan, Heinfried H. RadekeORCiDGND
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/05/26
Date of first Publication:2021/05/26
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/07/05
Tag:AKT signaling; CDK2; FOXO3; Ki-67; S1P lyase; SGPL1 knockout cell line; cell cycle; colon cancer; quiescence
Issue:11, art. 5682
Page Number:12
First Page:1
Last Page:12
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0