Sirtuin 1 knockdown inhibits glioma cell proliferation and potentiates temozolomide toxicity via facilitation of reactive oxygen species generation.

Abstract

Malignant glioma is one of the most common types of primary malignancies in the human central nervous system. Temozolomide (TMZ) is the most commonly used drug in clinical therapy of glioma; however, chemoresistance makes glioma difficult to cure and relapse likely. Sirtuin 1 (SIRT1) serves important roles in cell proliferation, differentiation and metabolism, but the role of SIRT1 in human glioma remains largely unexplored. In the present study, SIRT1 expression was assessed in human glioma tissues and cells. RNA interference and SIRT1 inhibitor were used to determine the effect of SIRT1 on glioma growth inhibition and glioma cell chemoresistance in vitro and in vivo. The levels of reactive oxygen species (ROS) in glioma cells were detected with the dihydroethidium probe following SIRT1 inhibition. The results demonstrated that SIRT1 was overexpressed in glioma tissues and cells, and patients with higher SIRT1 expression exhibited poorer prognosis. SIRT1 inhibition inhibited the proliferation of U87 and U251 cells. In addition, SIRT1 knockdown and SIRT1 inhibitor could significantly sensitize glioma cells to TMZ treatment in vitro and in vivo. The expression of Ki67 and p53 was demonstrated to be regulated by SIRT1. Finally, SIRT1 could regulate intracellular ROS generation in TMZ. In summary, SIRT1 was essential for glioma tumorigenesis and glioma cell chemoresistance. SIRT1 inhibition increased the sensitivity of glioma cells for TMZ via the facilitation of intracellular ROS generation, which suggested that SIRT1 may serve as a target for clinical therapy of glioma.