The nonlysosomal β‐glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells
| Autor: | Virginie Albinet, Thierry Levade, Carmen Bedia, Nathalie Andrieu-Abadie, Sonia-Caroline Sorli, Bruno Ségui, Christian Touriol, Josefina Casas, Nicolas Guilbaud, Alexandre Dubrac, Gemma Fabriàs, Sandra Colié |
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| Rok vydání: | 2012 |
| Předmět: |
Ceramide
Transplantation Heterologous Down-Regulation Mice Nude Apoptosis Ceramides Glucosylceramides Biochemistry Mice chemistry.chemical_compound Cell Line Tumor Genetics medicine Animals Humans Melanoma Molecular Biology Cell Proliferation Sphingolipids Cell growth beta-Glucosidase Endoplasmic reticulum Endoplasmic Reticulum Stress medicine.disease Sphingolipid Cell biology chemistry Tumor progression Unfolded Protein Response Unfolded protein response Glucosylceramidase Female Mutant Proteins Biotechnology |
| Zdroj: | The FASEB Journal. 27:489-498 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.12-215152 |
| Popis: | Glycosphingolipids, which are abundant at the surface of melanoma cells, play crucial roles in tumor progression. We investigated whether a newly described glycosphingolipid hydrolase, encoded by the GBA2 gene, can modulate human melanoma cell growth and death. GBA2 expression was quantified on melanoma cells by RT-qPCR. The antiproliferative effects of GBA2 were assessed in tumor cells expressing inducible GBA2 and in established melanoma xenografts. As a control an inducible catalytically inactive GBA2 mutant was generated. Sphingolipid levels were monitored by mass spectrometry; unfolded protein response (UPR) and apoptosis were assessed by Western blot and flow cytometry analyses, respectively. We report that GBA2 is down-regulated in melanoma; inducible expression of GBA2 affects endogenous sphingolipid metabolism by promoting glucosylceramide degradation (decrease by 78%) and ceramide generation; this is followed by a UPR that causes apoptosis, subsequent decreased anchorage-independent cell growth, and reduced in vivo tumor growth (by 40%); and all these events are abrogated when expressing a catalytically inactive GBA2. This study documents for the first time the antitumor activity of GBA2 and provides evidence for the role of nonlysosomal glucosylceramide breakdown as a source of bioactive ceramide and a mechanistic link between glycolipid catabolism and the UPR/death response of melanoma cells. |
| Databáze: | OpenAIRE |
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