TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ

Hui Lu,Jianmin Zhang,Qiuhong Duan,Changshu Ke,Fei Wang,Xiaofang Ni,Lin Liu,Huaxiong Pan,Ruijuan Xiu,Xinying Ji,Tengfei Ma,Ling Zou,Qin Tian,Wei Jia,Ping Yuan,Juanjuan Xiao,Feng Zhu

doi:10.1038/s41419-019-1805-9

Abstract

ULK1, the upper-most protein of the ULK1 complex, is emerging as a crucial node in autophagy induction. However, the regulation of ULK1 is not fully understood. In this study, we identified TOPK (T-LAK cell-originated protein kinase), an oncokinase, as a novel upstream kinase to phosphorylate ULK1. We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. In addition, we want to examine the initiation of autophagy because the reduction activity of ULK1 reduces the occurrence of autophagy. We demonstrated that TOPK could inhibit the initiation and progression of autophagy in glioma cells. Furthermore, TOPK inhibition increased the sensitivity of glioma cells to temozolomide (TMZ). This discovery provides insight into the problem of TMZ-resistance in GBM treatment.

Highlights

Glioblastoma multiforme (GBM) accounts for more than 50% of malignant gliomas
T-LAK cell initiation protein kinase (TOPK) inhibits autophagy in glioma cells Recent reports show that TOPK is a biomarker[30]
These findings suggested that TOPK might be related to autophagy

Summary

Introduction

Glioblastoma multiforme (GBM) accounts for more than 50% of malignant gliomas. The median survival time of GBM is 15 months because of being resistant to the therapy[1]. Temozolomide (TMZ) is the first-line chemotherapeutic drug of GBM. Only 45% of the patients were effective, most of the patients were resistant to TMZ in the course of therapy[2]. The mechanism of glioma resistance to TMZ is complex, including DDR3, EGFR overexpression[4], p53 mutations[5], and autophagy activity changes[6]. The role of autophagy in TMZ resistance is unclear. Liu T. et al found that Momelotinib induced autophagy and increased the sensitivity of glioma cells to TMZ7.

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