Ceramide-Enriched Membrane Domains Contribute to Targeted and Nontargeted Effects of Radiation through Modulation of PI3K/AKT Signaling in HNSCC Cells.

Riad Ladjohounlou,Alexandra Lauret,Arnaud Gauthier,Nicolas Magne,Safa Louati,Dominique Ardail,Gersende Alphonse,Claire Rodriguez-Lafrasse

doi:10.3390/ijms21197200

Abstract

We investigated the potential involvement of ceramide-enriched membrane domains in radiation-induced targeted and nontargeted effects using head and neck squamous cell carcinoma with opposite radiosensitivities. In radiosensitive SCC61 cells, the proportion of targeted effects was 34% and nontargeted effects killed 32% of cells. In contrast, only targeted effects (30%) are involved in the overall death of radioresistant SQ20B cells. We then demonstrated in SCC61 cells that nontargeted cell response was driven by the formation of the radiation-induced ceramide-enriched domain. By contrast, the existence of these platforms in SQ20B cells confers a permissive region for phosphatidylinositol-3-kinase (PI3K)/AKT activation. The disruption of lipid raft results in strong inhibition of PI3K/AKT signaling, leading to radiosensitization and apparition of nontargeted effects. These results suggest that ceramide-enriched platforms play a significant role in targeted and nontargeted effects during radiotherapy and that drugs modulating cholesterol levels may be a good alternative for improving radiotherapy effectiveness.

Highlights

Accumulated evidence shows that the biological effects of ionizing radiation can be expressed in cells that are not directly hit by particles but are in contact with or close vicinity to irradiated cells [1,2,3]
In addition to the direct effects of radiation, nontargeted effects were significant in radiosensitive SCC61 cells, involving lipid raft formation that could lead to cell death
The combination of MBCD + irradiation did not induce a significant release of cytokines in SQ20B donor cells. These results indicate that the presence of lipid rafts in the SQ20B cell membrane contributes to resistance to irradiation and the lack of radiation-induced nontargeted effects

Summary

Introduction

Accumulated evidence shows that the biological effects of ionizing radiation can be expressed in cells that are not directly hit by particles but are in contact with or close vicinity to irradiated cells [1,2,3]. This nontargeted effect of radiation, called bystander effect, has been mainly observed after low doses and is induced by low or high linear energy transfer (LET) radiation [4,5]. Other studies [20,21,22] have demonstrated the involvement of plasma membrane signaling in the bystander effect via the generation of ceramide (considered as a mediator of radiation), leading to activation of the mitogen-activated protein kinases (MAPK) and other pathways, which transduce amplified signals into the nucleus

Methods

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Discussion

Conclusion