한빛사 논문
Hui-Yun Hwang1,†, Yoon Sun Cho1,†, Jin Young Kim2, Ki Na Yun2, Jong Shin Yoo2, Eunhyeong Lee3, Injune Kim3 and Ho Jeong Kwon1,*
1Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
2Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chungbuk 28119, Korea
3Graduate 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.
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.
Keywords: autophagy; autophagonizer; target identification of label-free compound; target validation; autophagic flux; autophagy inhibition; lysosomal integrity function of Hsp70
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