PUBLICATION
BETA-GALACTOSYLCERAMIDASE PROMOTES MELANOMA GROWTH VIA MODULATION OF CERAMIDE METABOLISM
- Authors
- Belleri, M., Paganini, G., Coltrini, D., Ronca, R., Zizioli, D., Corsini, M., Barbieri, A., Grillo, E., Calza, S., Bresciani, R., Maiorano, E., Mastropasqua, M.G., Annese, T., Giacomini, A., Ribatti, D., Casas, J., Levade, T., Fabrias, G., Presta, M.
- ID
- ZDB-PUB-201002-220
- Date
- 2020
- Source
- Cancer research 80(22): 5011-5023 (Journal)
- Registered Authors
- Presta, Marco
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Differentiation/genetics
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Ceramides/metabolism*
- Down-Regulation
- Galactosylceramidase/genetics
- Galactosylceramidase/metabolism*
- Gene Silencing
- Humans
- Lung Neoplasms/secondary
- Melanocytes/cytology
- Melanocytes/enzymology
- Melanoma/metabolism
- Melanoma/pathology*
- Melanoma/secondary
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, SCID
- Neoplasm Invasiveness
- Skin Neoplasms/metabolism
- Skin Neoplasms/pathology*
- Sphingolipids/metabolism
- Sphingomyelin Phosphodiesterase/metabolism
- Up-Regulation
- Zebrafish
- PubMed
- 32998995 Full text @ Cancer Res.
Citation
Belleri, M., Paganini, G., Coltrini, D., Ronca, R., Zizioli, D., Corsini, M., Barbieri, A., Grillo, E., Calza, S., Bresciani, R., Maiorano, E., Mastropasqua, M.G., Annese, T., Giacomini, A., Ribatti, D., Casas, J., Levade, T., Fabrias, G., Presta, M. (2020) BETA-GALACTOSYLCERAMIDASE PROMOTES MELANOMA GROWTH VIA MODULATION OF CERAMIDE METABOLISM. Cancer research. 80(22):5011-5023.
Abstract
Disturbance of sphingolipid metabolism may represent a novel therapeutic target in metastatic melanoma, the most lethal form of skin cancer. Beta-galactosylceramidase (GALC) removes beta-galactose from galactosylceramide and other sphingolipids. In this study, we show that downregulation of galcb, a zebrafish orthologue of human GALC, affects melanoblast and melanocyte differentiation in zebrafish embryos, suggesting a possible role for GALC in melanoma. On this basis, the impact of GALC expression in murine B16-F10 and human A2058 melanoma cells was investigated following its silencing or upregulation. Galc knockdown hampered growth, motility, and invasive capacity of B16-F10 cells and their tumorigenic and metastatic activity when grafted in syngeneic mice or zebrafish embryos. Galc-silenced cells displayed altered sphingolipid metabolism and increased intracellular levels of ceramide, paralleled by a non-redundant upregulation of Smpd3, which encodes for the ceramide-generating enzyme neutral sphingomyelinase 2. Accordingly, GALC downregulation caused SMPD3 upregulation, increased ceramide levels, and inhibited the tumorigenic activity of human melanoma A2058 cells, whereas GALC upregulation exerted opposite effects. In concordance with information from melanoma database mining, RNAscope analysis demonstrated a progressive increase of GALC expression from common nevi to stage IV human melanoma samples that was paralleled by increases in microphtalmia transcription factor and tyrosinase immunoreactivity inversely related to SMPD3 and ceramide levels. Overall, these findings indicate that GALC may play an oncogenic role in melanoma by modulating the levels of intracellular ceramide, thus providing novel opportunities for melanoma therapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping