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Gangliosides protect human melanoma cells from ionizing radiation-induced clonogenic cell death
C P Thomas1, A Buronfosse, V Combaret
1Laboratoire de Cancérologie Expérimentale (INSERM ex U. 218) Centre Léon Bérard, Lyon, France.
Abstract:
With an experimental model of spontaneous lung metastases of melanoma developed in this laboratory, a range of sublines (variants and clones) with different metastatic potential and ganglioside expression was established from a single human melanoma cell line M4Be. Using an in vitro clonogenic assay and provided that cells were cultured for no more than five passages, variations in cellular radioresistance of M4Be and seven sublines derived from M4Be were detected. This study shows a positive correlation between the cell intrinsic radioresistance of M4Be and its seven sublines and their total ganglioside content. More precisely, the proportion of radioresistant cells in M4Be and the seven sublines correlated with the number of cells determined by flow cytometry that were positively labelled with a monoclonal antibody directed to GD3 disialoganglioside. Blocking the cellular biosynthesis of gangliosides with the inhibitor Fumonisin B1 or cleaving with Vibrio cholerae neuraminidase the cell surface ganglioside-bound sialic acid in a radioresistant poorly metastatic subline increased its radiosensitivity in vitro. In contrast, enrichment of a radiosensitive metastatic subline with exogenous bovine brain GM1 increased its radioresistance in vitro. These results suggest that, in the radiation dose range important for radioprotection (0-1 Gy), membrane gangliosides radioprotect human melanoma cells in vitro.
Insights
Melanoma cells
Area of Science:
- Oncology
- Cancer Biology
- Radiation Oncology
Background:
- Melanoma exhibits variable metastatic potential and ganglioside expression.
- Sublines derived from the M4Be human melanoma cell line were established to study these variations.
- Cellular radioresistance is a critical factor in melanoma treatment outcomes.
Purpose of the Study:
- To investigate the correlation between ganglioside expression and cellular radioresistance in melanoma.
- To determine the role of specific gangliosides, particularly GD3, in melanoma cell radioresistance.
- To explore the potential of targeting gangliosides for modulating melanoma radiosensitivity.
Main Methods:
- Establishment of melanoma sublines with varying metastatic potential and ganglioside expression from the M4Be cell line.
- In vitro clonogenic assays to assess cellular radioresistance across different melanoma sublines.
- Flow cytometry using monoclonal antibodies to quantify GD3 disialoganglioside expression.
- Pharmacological manipulation of ganglioside biosynthesis (Fumonisin B1) and cell surface sialic acid (Vibrio cholerae neuraminidase).
- In vitro experiments involving enrichment with exogenous gangliosides (GM1).
Main Results:
- A positive correlation was observed between intrinsic radioresistance and total ganglioside content in M4Be melanoma cells and their sublines.
- The proportion of radioresistant cells directly correlated with GD3 disialoganglioside levels.
- Inhibition of ganglioside biosynthesis or removal of cell surface sialic acid increased radiosensitivity in radioresistant melanoma cells.
- Enrichment with exogenous GM1 ganglioside enhanced radioresistance in a radiosensitive melanoma subline.
Conclusions:
- Membrane gangliosides, including GD3, play a significant role in conferring radioresistance to human melanoma cells in vitro.
- Gangliosides may act as radioprotective agents for melanoma cells within clinically relevant radiation dose ranges (0-1 Gy).
- Targeting ganglioside metabolism or expression presents a potential strategy for overcoming radioresistance in melanoma treatment.
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