Notch1 and Major Vault Proteins Modulate Temozolomide Resistance in Glioblastoma

Abstract

The development of resistance to chemotherapy in the case of aggressive glioblastoma multiforme (GBM) presents a significant treatment challenge. Dysregulation of the Notch signalling pathway promotes tumour proliferation in GBM cells. This study was that targeting the Notch signalling pathway could be a potential therapeutic approach for GBM. Initially, temozolomide-(TMZ)-resistant GBM cells were generated, and the effect of Notch1 on the expression of multiple resistance proteins within these cells was investigated. Subsequently, the expression of Notch-1 in GBM cells was reduced using siRNA. Results revealed a significant reduction in TMZ sensitivity in TMZ-resistant GBM cells, accompanied by a substantial increase in the expression of major vault protein-(MVP), O6-methylguanine-DNA-methyltransferase-(MGMT), and ATP-binding-cassette transporter-G2-(ABCG2). Furthermore, TMZ-resistant U87-R and U251-R cells exhibited higher proliferation rates compared to their parental control cells (U87 and U251). Additionally, we observed that downregulating Notch-1 signalling inhibited the proliferation of TMZ-resistant U87-R and U251-R cells. This downregulation led to the inactivation of MGMT, ABCG2, and MVP. Importantly, it increased chemosensitivity to TMZ, particularly by downregulating MVP expression. Consequently, Notch1 could serve as a potential therapeutic target for GBM cells and may be effective in preventing TMZ resistance by targeting MVP, as well as MGMT and ABCG2 in GBM cells.