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

Abstract

Background: It is now established that radiation can affect membranes of mammalian cells in several ways. Depending on the degree of conditioning and mobility of phospholipidic molecules within the plasma membrane, cells exhibit different degrees of sensitivity to radiation. Methods: Here, we investigated the potential involvement of ceramide-enriched membrane domains in radiation-induced targeted and nontargeted effects. Two cell lines of head and neck squamous cell carcinoma (HNSCC) with opposite radiosensitivity were used. Findings: In radiosensitive SCC61 cells, the proportion of targeted effects was 34% and nontargeted effects killed about 32% of cells. In contrast, only targeted effects (30%) are involved in the overall death of radioresistant SQ20B cells. Using methyl-β-cyclodextrin (MBCD), a lipid raft disruptor, we found in SCC61 cells that the formation of a radiation-induced ceramide-enriched domain was suppressed which resulted in a significant reduction of nontargeted effects. By contrast, the existence of ceramide-enriched platforms in radioresistant SQ20B cells, blocks the response to bystander signaling and also confers a protective effect against radiation. We also showed that lipid raft disruption was followed with strong inhibition of PI3K/AKT signaling in SQ20B cells. Combining wortmannin, a PI3K inhibitor with radiation resulted in an increase of cell death and induction of nontargeted response when compared with radiation alone in these cells. Interpretation: These results show in HNSCC cells that ceramide-enriched platforms play a significant role in targeted and nontargeted effect during radiotherapy. They also suggest the potential utility of combining drugs modulating cholesterol levels such as statins with radiation to improve the HNSCC treatment. Funding: This study was supported by LabEx Primes (ANR-11 LABX-0063). Declaration of Interests: No potential conflicts of interest are disclosed.