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Open AccessFeature PaperArticle

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

1
Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
2
Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chungbuk 28119, Korea
3
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(3), 543; https://doi.org/10.3390/cancers12030543
Received: 10 February 2020 / Revised: 22 February 2020 / Accepted: 25 February 2020 / Published: 27 February 2020
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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. View Full-Text
Keywords: autophagy; autophagonizer; target identification of label-free compound; target validation; autophagic flux; autophagy inhibition; lysosomal integrity function of Hsp70 autophagy; autophagonizer; target identification of label-free compound; target validation; autophagic flux; autophagy inhibition; lysosomal integrity function of Hsp70
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    Doi: doi:10.20944/preprints202002.0134.v1
MDPI and ACS Style

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.

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