Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Arylquin 1, a potent Par-4 secretagogue, induces lysosomal membrane permeabilization-mediated non-apoptotic cell death in cancer cells

  • Min, Kyoung-jin (Department of Immunology, School of Medicine, Keimyung University) ;
  • Shahriyar, Sk Abrar (Department of Immunology, School of Medicine, Keimyung University) ;
  • Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University)
  • Received : 2019.07.19
  • Accepted : 2019.08.28
  • Published : 2020.04.15
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Abstract

Arylquin 1, a small-molecule prostate-apoptosis-response-4 (Par-4) secretagogue, targets vimentin to induce Par-4 secretion. Secreted Par-4 binds to its receptor, 78-kDa glucose-regulated protein (GRP78), on the cancer cell surface and induces apoptosis. In the present study, we investigated the molecular mechanisms of arylquin 1 in cancer cell death. Arylquin 1 induces morphological changes (cell body shrinkage and cell detachment) and decreases cell viability in various cancer cells. Arylquin 1-induced cell death is not inhibited by apoptosis inhibitors (z-VAD-fmk, a pan-caspase inhibitor), necroptosis inhibitors (necrostatin-1), and paraptosis inhibitors. Furthermore, arylquin 1 significantly induces reactive oxygen species levels, but antioxidants [N-acetyl-ʟ-cysteine and glutathione ethyl ester] do not inhibit arylquin 1-induced cell death. Furthermore, Par-4 knock-down by small interfering RNA confers no effect on cytotoxicity in arylquin 1-treated cells. Interestingly, arylquin 1 induces lysosomal membrane permeabilization (LMP), and cathepsin inhibitors and overexpression of 70-kDa heat shock protein (HSP70) markedly prevent arylquin 1-induced cell death. Therefore, our results suggest that arylquin 1 induces non-apoptotic cell death in cancer cells through the induction of LMP.

Keywords

Acknowledgement

This work was supported by an NRF Grant funded by the Korea Government (MSIP) (2014R1A5A2010008 and NRF-2019R1A2C2005921) and a 2018 Scholar Research Grant from Keimyung University.

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