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Published on: April 7, 2017
GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular
Laura E Clark1, Amanda J G Dickinson1, Santiago Lima1,2
1Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA.
Abstract:
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.
Insights
In cancer, increased activity of glucosylceramidase beta 1 (GBA) promotes tumor growth and resistance to therapy. Reducing GBA levels reverses these effects, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Biochemistry
- Cancer Biology
- Molecular Oncology
Background:
- Glycosphingolipids (GSLs) are key plasma membrane molecules influencing cancer development and treatment response.
- GSLs modulate receptor tyrosine kinases (RTKs) involved in epithelial-mesenchymal transition (EMT).
- Glucosylceramidase beta 1 (GBA) is a critical enzyme regulating GSL degradation.
Purpose of the Study:
- To investigate the role of GBA in cancer progression and chemoresistance.
- To explore the therapeutic potential of targeting GBA in cancer treatment.
- To understand how GBA influences RTK signaling and EMT via lipid profiles.
Main Methods:
- Analysis of GBA copy number and expression in cancer.
- Depletion of GBA in squamous cell carcinoma cell lines.
- Assessment of cellular phenotypes (invasion, migration, EMT markers).
- Evaluation of RTK activation and chemotherapeutic sensitivity.
- Untargeted lipidomics to analyze sphingolipid and GSL profiles.
Main Results:
- GBA copy number amplifications and increased expression are prevalent in cancer.
- GBA depletion induced a mesenchymal-to-epithelial shift, reducing invasion and migration.
- GBA depletion enhanced chemotherapeutic sensitivity and decreased RTK activation.
- Lipidomic analysis revealed significant alterations in sphingolipids and GSLs upon GBA depletion.
Conclusions:
- Elevated GBA activity in cancer sustains EMT and chemoresistance.
- GBA modulates RTK activity and signaling through its impact on cellular lipid profiles.
- Targeting GBA represents a promising therapeutic strategy for overcoming cancer progression and chemoresistance.
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