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Published on: February 3, 2017
TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ
Hui Lu1, Juanjuan Xiao1, Changshu Ke2
1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, PR China.
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.
Insights
T-LAK cell-originated protein kinase (TOPK) phosphorylates and inhibits Unc-51 like autophagy activating kinase 1 (ULK1), suppressing autophagy in glioma cells. TOPK inhibition enhances temozolomide sensitivity, offering new glioblastoma treatment strategies.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Unc-51 like autophagy activating kinase 1 (ULK1) is a key regulator of autophagy induction.
- The precise regulatory mechanisms governing ULK1 activity remain incompletely understood.
- Autophagy plays a critical role in cellular homeostasis and disease, including cancer.
Purpose of the Study:
- To identify novel upstream kinases regulating ULK1.
- To investigate the role of T-LAK cell-originated protein kinase (TOPK) in ULK1 regulation and autophagy.
- To explore the therapeutic potential of targeting TOPK in glioma treatment.
Main Methods:
- Co-immunoprecipitation assays to confirm protein-protein interactions.
- In vitro kinase assays to assess phosphorylation.
- Western blotting to detect protein levels and phosphorylation status.
- Cell viability assays and autophagy flux analysis in glioma cell lines.
Main Results:
- T-LAK cell-originated protein kinase (TOPK) was identified as a novel upstream kinase for ULK1.
- TOPK directly phosphorylates ULK1 at Ser469, Ser495, and Ser533, reducing ULK1 activity and stability.
- TOPK inhibits autophagy initiation and progression in glioma cells.
- Inhibition of TOPK enhances glioma cell sensitivity to temozolomide (TMZ).
Conclusions:
- TOPK acts as a negative regulator of ULK1 and autophagy in glioma cells.
- Targeting TOPK represents a potential therapeutic strategy to overcome temozolomide resistance in glioblastoma (GBM).
- This study elucidates a novel mechanism in autophagy regulation with implications for cancer therapy.
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