Autophagic inhibition via lysosomal integrity dysfunction leads to antitumor activity in glioma treatment

Hui Yun Hwang, Yoon Sun Cho, Jin Young Kim, Ki Na Yun, Jong Shin Yoo, Eunhyeong Lee, Injune Kim, Ho Jeong Kwon

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors are shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets, we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC–MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.

Original languageEnglish
Article number543
JournalCancers
Volume12
Issue number3
DOIs
Publication statusPublished - 2020 Mar

Bibliographical note

Funding Information:
Funding: This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2012M3A9D1054520, 2015K1A1A2028365, 2016K2A9A1A03904900, 2018M3A9C4076477) and Brain Korea 21 Plus Project, Republic of Korea and ICONS (Institute of Convergence Science), Yonsei University.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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