GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile

Glycosphingolipids (GSL) are plasma membrane components that influence molecular processes involved in cancer initiation, progression, and therapeutic responses. They also modulate receptor tyrosine kinases involved in EMT. Therefore, understanding the mechanisms that regulate GSLs in cancer has imp...

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Main Authors: Laura E. Clark, Amanda J. G. Dickinson, Santiago Lima
Format: Article
Language:English
Published: MDPI AG 2023-07-01
Series:Cells
Subjects:
Online Access:https://www.mdpi.com/2073-4409/12/14/1886
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author Laura E. Clark
Amanda J. G. Dickinson
Santiago Lima
author_facet Laura E. Clark
Amanda J. G. Dickinson
Santiago Lima
author_sort Laura E. Clark
collection DOAJ
description Glycosphingolipids (GSL) are plasma membrane components that influence molecular processes involved in cancer initiation, progression, and therapeutic responses. They also modulate receptor tyrosine kinases involved in EMT. Therefore, understanding the mechanisms that regulate GSLs in cancer has important therapeutic potential. One critical regulator of GSLs is the lysosomal glucosylceramidase β1 (GBA) that catalyzes the last step in GSL degradation. We show that, in cancer, GBA copy number amplifications and increased expression are widespread. We show that depleting GBA in squamous cell carcinoma cell lines results in a mesenchymal-to-epithelial shift, decreased invasion and migration, increased chemotherapeutic sensitivity, and decreased activation of receptor tyrosine kinases that are involved in regulating EMT. Untargeted lipidomics shows that GBA depletion had significant effects on sphingolipids and GSLs, suggesting that increased GBA activity in cancer sustains EMT and chemoresistance by modulating receptor tyrosine kinase activity and signaling via effects on the cellular lipid profile.
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spelling doaj.art-8ef378310982432fa2667f5da6e7c7bb2023-11-18T18:46:34ZengMDPI AGCells2073-44092023-07-011214188610.3390/cells12141886GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid ProfileLaura E. Clark0Amanda J. G. Dickinson1Santiago Lima2Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USADepartment of Biology, Virginia Commonwealth University, Richmond, VA 23284, USADepartment of Biology, Virginia Commonwealth University, Richmond, VA 23284, USAGlycosphingolipids (GSL) are plasma membrane components that influence molecular processes involved in cancer initiation, progression, and therapeutic responses. They also modulate receptor tyrosine kinases involved in EMT. Therefore, understanding the mechanisms that regulate GSLs in cancer has important therapeutic potential. One critical regulator of GSLs is the lysosomal glucosylceramidase β1 (GBA) that catalyzes the last step in GSL degradation. We show that, in cancer, GBA copy number amplifications and increased expression are widespread. We show that depleting GBA in squamous cell carcinoma cell lines results in a mesenchymal-to-epithelial shift, decreased invasion and migration, increased chemotherapeutic sensitivity, and decreased activation of receptor tyrosine kinases that are involved in regulating EMT. Untargeted lipidomics shows that GBA depletion had significant effects on sphingolipids and GSLs, suggesting that increased GBA activity in cancer sustains EMT and chemoresistance by modulating receptor tyrosine kinase activity and signaling via effects on the cellular lipid profile.https://www.mdpi.com/2073-4409/12/14/1886glucosylceramidegangliosidessquamous cell carcinomachemoresistanceEMTMET
spellingShingle Laura E. Clark
Amanda J. G. Dickinson
Santiago Lima
GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
Cells
glucosylceramide
gangliosides
squamous cell carcinoma
chemoresistance
EMT
MET
title GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
title_full GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
title_fullStr GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
title_full_unstemmed GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
title_short GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
title_sort gba regulates emt met and chemoresistance in squamous cell carcinoma cells by modulating the cellular glycosphingolipid profile
topic glucosylceramide
gangliosides
squamous cell carcinoma
chemoresistance
EMT
MET
url https://www.mdpi.com/2073-4409/12/14/1886
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