TAILIEUCHUNG - Báo cáo khoa học: Antisense glutaminase inhibition decreases glutathione antioxidant capacity and increases apoptosis in Ehrlich ascitic tumour cells

Glutamine is an essential amino acid in cancer cells and is required for the growth of many other cell types. Glutami-nase activity is positively correlated with malignancy in tumours andwith growth rate in normal cells. In the present work, Ehrlich ascites tumour cells, and their derivative, cells, expressing antisense glutaminase mRNA, were assayed for apoptosis induced by methotrexate and hydrogen peroxide. It is shown that Ehrlich ascites tumour cells, expressing antisense mRNA for glutaminase, contain lower levels of glutathione than normal ascites cells. In addition, cells contain a higher number of apop-totic cells and are more sensitive to both methotrexate and hydrogen peroxide toxicity than normal cells | Eur. J. Biochem. 271 4298-4306 2004 FEBS 2004 doi Antisense glutaminase inhibition decreases glutathione antioxidant capacity and increases apoptosis in Ehrlich ascitic tumour cells Jorge Lora Francisco J. Alonso Juan A. Segura Carolina Lobo Javier Marquez and Jose M. Mates Departamento de Biologia Molecular y Bioquimica Laboratorio de Quimica de Proteinas Facultad de Ciencias Universidad de Malaga Spain Glutamine is an essential amino acid in cancer cells and is required for the growth of many other cell types. Glutaminase activity is positively correlated with malignancy in tumours and with growth rate in normal cells. In the present work Ehrlich ascites tumour cells and their derivative cells expressing antisense glutaminase mRNA were assayed for apoptosis induced by methotrexate and hydrogen peroxide. It is shown that Ehrlich ascites tumour cells expressing antisense mRNA for glutaminase contain lower levels of glutathione than normal ascites cells. In addition cells contain a higher number of apop-totic cells and are more sensitive to both methotrexate and hydrogen peroxide toxicity than normal cells. Taken together these results provide insights into the role of glutaminase in apoptosis by demonstrating that the expression of antisense mRNA for glutaminase alters apoptosis and glutathione antioxidant capacity. Keywords antisense apoptosis glutaminase glutamine glutathione. Phosphate-activated glutaminase GA EC has a critical role in tumours and rapidly dividing cells and its activity is correlated with malignancy 1 . Ehrlich ascites tumour cells EATC transfected with the pcDNA3 vector containing an antisense segment kb of rat kidney GA showed impairment in the rate of growth and a reduction in the GA protein level when compared with the parental cells. Cells were selected after culture for 2-3 weeks. Following G418 selection 12 drug-resistant neo clones were picked randomly from different plates

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