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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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Detalles Bibliográficos
Autores principales: Clark, Laura E., Dickinson, Amanda J. G., Lima, Santiago
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378370/
https://www.ncbi.nlm.nih.gov/pubmed/37508550
http://dx.doi.org/10.3390/cells12141886
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author Clark, Laura E.
Dickinson, Amanda J. G.
Lima, Santiago
author_facet Clark, Laura E.
Dickinson, Amanda J. G.
Lima, Santiago
author_sort Clark, Laura E.
collection PubMed
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 pubmed-103783702023-07-29 GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile Clark, Laura E. Dickinson, Amanda J. G. Lima, Santiago Cells Article 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. MDPI 2023-07-18 /pmc/articles/PMC10378370/ /pubmed/37508550 http://dx.doi.org/10.3390/cells12141886 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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/).
spellingShingle Article
Clark, Laura E.
Dickinson, Amanda J. G.
Lima, Santiago
GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378370/
https://www.ncbi.nlm.nih.gov/pubmed/37508550
http://dx.doi.org/10.3390/cells12141886
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