RESUMO
Carnosine is an endogenous dipeptide with antiproliferative properties. Here we show that carnosine selectively inhibits proliferation of human glioblastoma cells (U-118-MG) compared to breast (MB231) and oral (Cal27 and FaDu) cancer cells. Carnosine-induced inhibition of U-118-MG proliferation is associated with a significant: decrease in cellular reactive oxygen species levels, increase in manganese superoxide dismutase (MnSOD) and increase in cyclin B1 expression resulting in G2-block. We conclude that the antiproliferative property of carnosine is due to its ability to enhance MnSOD and cyclin B1 expression. These results will be of significance to the potential application of carnosine in brain cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Carnosina/farmacologia , Ciclina B1/genética , Neuroglia/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Superóxido Dismutase/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/agonistas , Ciclina B1/metabolismo , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neuroglia/metabolismo , Neuroglia/patologia , Especificidade de Órgãos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Manganese superoxide dismutase (MnSOD) is a nuclear encoded and mitochondrial matrix-localized redox enzyme that is known to regulate the cellular redox environment. Cellular redox environment changes during transitions between quiescent and proliferative cycles. Human MnSOD has two poly(A) sites resulting in two transcripts: 1.5 and 4.2 kb. The present study investigates if the 3'-untranslated region (UTR) of MnSOD regulates its expression during transitions between quiescent and proliferating cycles, and in response to radiation. A preferential increase in the levels of the 1.5-kb MnSOD transcript was observed in quiescent cells, whereas the abundance of the longer transcript showed a direct correlation with the percentage of S-phase cells. The log-transformed expression ratio of the longer to the shorter transcript was also higher in proliferating normal and cancer cells. Deletion and reporter assays showed a significant decrease in reporter activity in constructs carrying multiple AU-rich sequence that are present in the 3'-UTR of the longer MnSOD transcript. Overexpression of the MnSOD 3'-UTR representing the longer transcript enhanced endogenous MnSOD mRNA levels, which was associated with an increase in MnSOD protein levels and a decrease in the percentage of S-phase cells. Irradiation increases the mRNA levels of the 1.5-kb MnSOD transcript, which was consistent with a significant increase in the reporter activity of the construct carrying the 3'-UTR of the shorter transcript. We conclude that the 3'-UTR of MnSOD regulates MnSOD expression in response to different growth states and radiation.