RESUMO
BACKGROUND/AIM: This study aimed to elucidate the role of glutathione peroxidase 4 (GPX4) on the sterol regulatory element binding proteins (SREBPs)-proliferation pathway in oral cancer cells, and determine its protein expression in oral cancer tissues. MATERIALS AND METHODS: Quantitative RT-PCR and immunoblot analysis were carried out. Cell viability assay, apoptosis detection assay, immunohistochemistry and GPX4 knockdown were performed. RESULTS: The levels of both GPX4 mRNA and protein were highest in SAS cells. GPX4 knockdown in SAS cells, a human oral squamous cell carcinoma cell line, using GPX4 siRNA resulted in a reduction in cell number, which appeared to be due to non-apoptotic cell death such as ferroptosis. Furthermore, SREBP was clearly down-regulated by GPX4 knockdown in SAS cells. Immunopositivity for GPX4 was revealed on the membrane of human oral squamous cell carcinoma cells, and this was correlated with p53 immunoreactivity. CONCLUSION: GPX4 appears to play an important role in oral cancer proliferation.
Assuntos
Proliferação de Células , Neoplasias Bucais/enzimologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Ferroptose , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Mangosteen (Garcinia mangostana) is a tree found in South-East Asia and the pericarp of its fruit has been used in folk medicine for the treatment of many human illnesses. Mangosteen fruit rinds contain a high concentration of xanthone, which is a type of polyphenol. One type of xanthone, α-mangostin, has been reported to exert chemopreventive effects against chemically-induced colon cancer through the decrease of c-Myc expression, suppressing tumor growth in a mouse model of mammary cancer. A recent study demonstrated the inhibitive effect of α-mangostin on the growth of prostate cancer. However, it remains unclear whether α-mangostin induces cell death in oral cancer. The present study examined the impact of α-mangostin on human oral squamous cell carcinoma (HOSCC). Firstly we analyzed the expression of c-Myc in five HOSCC cell lines. The highest expression level of c-Myc mRNA was observed in SAS cells and the lowest in HSC-4 cells. Therefore, SAS cells were treated with α-mangostin, which was found to exert a weak cytocidal effect. Since α-mangostin has been reported to exert synergistic effects on cancers when combined with anticancer drugs, we attempted to evaluate such synergistic effects of α-mangostin when used with a cytokine, tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL). We found that the combination of α-mangostin with TRAIL induced apoptosis of SAS cells through the mitochondrial pathway via activation of caspase-9 and -3/7, following release of cytochrome c. This apoptosis was induced by S/G2/M-phase arrest. Immunopositivity for c-Myc was observed in the cytoplasm of tumor cells in 16 (40%) of the 40 cases of HOSCC. These data revealed that the combination of α-mangostin and TRAIL may have a considerable potential for the treatment of oral cancer.
