fumarates and Carcinoma

EBV infection is a recognized epigenetic driver of carcinogenesis. We previously showed that EBV could protect cancer cells from TNF-induced necroptosis. This study aims to explore the epigenetic mechanisms allowing cancer cells with EBV infection to escape from RIP3-dependent necroptosis.

Topics: Aged; Animals; Carcinogenesis; Carcinoma; Cell Line, Tumor; Cellular Reprogramming; DNA Methylation; Epithelial Cells; Female; Fumarates; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human; Heterografts; Host-Pathogen Interactions; Humans; Ketoglutaric Acids; Male; Mice; Middle Aged; Nasopharyngeal Neoplasms; Nasopharynx; Necroptosis; Promoter Regions, Genetic; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; Survival Analysis; Viral Matrix Proteins

Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. The major focus of this work was to design a transient glutathione depleting strategy during the course of irradiation of HNSCC in order to overcome their radioresistance associated with redox adaptation.. Treatment of SQ20B cells with dimethylfumarate (DMF), a GSH-depleting agent, and L-Buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis 4 h before a 10 Gy irradiation led to the lowering of the endogenous GSH content to less than 10% of that in control cells and to the triggering of radiation-induced apoptotic cell death. The sequence of biochemical events after GSH depletion and irradiation included ASK-1 followed by JNK activation which resulted in the triggering of the intrinsic apoptotic pathway through Bax translocation to mitochondria.. This transient GSH depletion also triggered radiation-induced cell death in SQ20B stem cells, a key event to overcome locoregional recurrence of HNSCC. Finally, our in vivo data highlight the relevance for further clinical trials of endogenous redox modulation to enhance the cytotoxic effects of radiotherapy.

Topics: Adaptation, Physiological; Apoptosis; bcl-2-Associated X Protein; Buffers; Buthionine Sulfoximine; Carcinoma; Carcinoma, Squamous Cell; Cell Line, Tumor; Dimethyl Fumarate; Fumarates; Glutathione; Head and Neck Neoplasms; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 5; Neoplasms, Squamous Cell; Neoplastic Stem Cells; Oxidation-Reduction; Squamous Cell Carcinoma of Head and Neck