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

Cell Death & Disease
Hui LuFeng Zhu

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.

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Citations

Oct 13, 2020·Journal of Cellular Physiology·Jiafeng LiKailiang Zhou
Dec 15, 2020·European Journal of Pharmacology·Milad AshrafizadehMasoud Najafi
Apr 11, 2020·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Jing-Xuan XuXin-Ping Luan
May 11, 2021·Autophagy·Mariya LichevaFulvio Reggiori
Aug 31, 2021·International Journal of Cancer. Journal International Du Cancer·Debmita Chatterjee, Oishee Chakrabarti

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
transmission electron microscopy
FACS
pull down
pull-down
flow cytometry
transfection
ubiquitination

Software Mentioned

Flowjo
Protein Pilot
NetPhos2
Prism
Image Lab
Image J

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