ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression

Abstract

Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.

Lidocaine attenuates TMZ resistance and inhibits cell migration by modulating the MET pathway in glioblastoma cells

“…2D ). During stressful conditions such as starvation or chemotherapy, cancer cells may activate certain signaling pathways that give them an advantage in survival ( 37 ). Therefore, U87MG and U87MGR cells were cultured in serum-free medium for 24 and 48 h and the changes in HGF expression and MET activation upon starvation were assessed.…”

“…To verify the present findings, another GBM cell line, DBTRG-05MG cells, were selected to investigate the effect of lidocaine on the MET pathway and further analyze its relationship with TMZ sensitivity and cell migration. This choice was based on a previous study by the authors, which revealed that DBTRG-05MG cells exhibit a high level of resistance to TMZ ( 37 ). The DBTRG-05MG cells were cultured in a serum-free medium for 24 and 48 h, and the impact of starvation on MET activation was evaluated using western blotting.…”