Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment

Hui-Yun Hwang
ORCID logo ,
Yoon Sun Cho
,
Jin Young Kim
,
Ki Na Yun
,
Jong Shin Yoo
,
Eunhyeong Lee
,
Injune Kim
,
Ho Jeong Kwon
* ORCID logo
Version 1 : Received: 10 February 2020 / Approved: 11 February 2020 / Online: 11 February 2020 (09:03:51 CET)

A peer-reviewed article of this Preprint also exists.

Hwang, H.-Y.; Cho, Y.S.; Kim, J.Y.; Yun, K.N.; Yoo, J.S.; Lee, E.; Kim, I.; Kwon, H.J. Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment. Cancers 2020, 12, 543. Hwang, H.-Y.; Cho, Y.S.; Kim, J.Y.; Yun, K.N.; Yoo, J.S.; Lee, E.; Kim, I.; Kwon, H.J. Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment. Cancers 2020, 12, 543.

Abstract

Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors 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.

Keywords

autophagy; autophagonizer; target identification of label-free compound; target validation; autophagic flux; autophagy inhibition; lysosomal integrity function of Hsp70

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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