Pharmacological inhibition of PHGDH enhances temozolomide efficacy via decreasing MGMT expression and ROS-induced DNA damage in glioblastoma

Abstract

Objective: To investigate whether and how pharmacological inhibition of PHGDH enhances temozolomide efficacy in glioblastoma. Method: MTT, flowcytometry and colony formation assays were used to measure the anti-proliferative and pro-apoptotic effects of NCT503 treatment alone or in combination with temozolomide. Flowcytometry was used to detect the intracellular ROS levels. Western blot was performed to measure MGMT expression levels and molecular mechanisms. Result: NCT503 or temozolomide treatment alone showed limited effects on proliferation and apoptosis of glioblastoma cells. But when combined together, NCT503 synergistically augmented the anti-proliferative ad pro-apoptoticeffects of temozolomide. Mechanistically, on the one hand, NCT503 decreased MGMT expressions by inhibiting beta-catenin pathway. On the other hand, intracellular ROS levels were elevated after NCT03 treatment or TMZ treatment alone and to a greater extent when combined and addition of N-acetylcysteine (NAC) partially rescued the effects. Conclusion: Pharmacological inhibition of PHGDH enhances temozolomide efficacy via decreasing MGMT expression by inhibiting beta-catenin pathway and ROS-induced DNA damage in glioblastoma.