Turkish Neurosurgery 2024 , Vol 34 , Num 1
Multiple Pathway-Dephosphorylated ASK-1 Confers Temozolomide-Resistance to Human Glioma Cells
Kai GAO1,Kun SHE1,Jie FAN2,Lianbin SHAO1,Zhiwu JI1
1Affiliated Hospital of Hebei University of Engineering, Department of Neurosurgery I, Handan 056002, Hebei, China
2Affiliated Hospital of Hebei University of Engineering, Clinical Lab, Handan 056002, Hebei, China
DOI : 10.5137/1019-5149.JTN.41212-22.1 AIM: To elucidate the function of ASK-1 and the role of its modulators in the induction of Temozolamide (TMZ) resistance in glioma and the underlying mechanism.

MATERIAL and METHODS: ASK-1 phosphorylation, the IC50 of TMZ, cell viability, and apoptosis were assessed in the U87 and U251 glioma cell lines and the derived TMZ-resistant cell lines U87-TR and U251-TR. We then blocked ASK-1 function, either with an inhibitor or by overexpression of multiple ASK-1 upstream modulators, to further explore the role of ASK-1 in TMZ-resistant glioma.

RESULTS: TMZ-resistant glioma cells showed high IC50 values of TMZ, high survival, and low levels of apoptosis following the TMZ challenge. ASK-1 phosphorylation, but not protein expression, was higher in U87 and U251 cells than in TMZ-resistant glioma cells exposed to TMZ. The addition of the ASK-1 inhibitor selonsertib (SEL) resulted in the dephosphorylation of ASK-1 in U87 and U251 cells after the TMZ challenge. SEL treatment increased the TMZ resistance of U87 and U251 cells, as evidenced by the increased IC50 and cell survival rate and low apoptosis rate. Overexpression of some ASK-1 upstream suppressors [Thioredoxin (Trx), protein phosphatase 5 (PP5), 14-3-3, and cell division cycle 25C (Cdc25C)] led to various degrees of ASK-1 dephosphorylation and a TMZresistant phenotype in U87 and U251 cells.

CONCLUSION: Dephosphorylation of ASK-1 induced TMZ resistance in human glioma cells, and several ASK-1 upstream suppressors, including Trx, PP5, 14-3-3, and Cdc25C, are involved in this phenotypic change induced by dephosphorylation of ASK-1. Keywords : Glioma, TMZ, ASK-1, drug resistance, SEL

Corresponding author : Zhiwu JI, jizhiwu88@126.com