Advertisement

Arylquin 1, a potent Par-4 secretagogue, induces lysosomal membrane permeabilization-mediated non-apoptotic cell death in cancer cells

  • Kyoung-jin Min
  • Sk Abrar Shahriyar
  • Taeg Kyu KwonEmail author
Original Article
  • 2 Downloads

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-l-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

Arylquin 1 Non-apoptotic cell death Lysosomal membrane permeabilization Prostate‐apoptosis‐response‐4 Cell death 

Notes

Acknowledgements

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.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Burikhanov R, Sviripa VM, Hebbar N, Zhang W, Layton WJ, Hamza A, Zhan CG, Watt DS, Liu C, Rangnekar VM (2014) Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat Chem Biol 10:924–926CrossRefGoogle Scholar
  2. 2.
    Sviripa VM, Burikhanov R, Obiero JM, Yuan Y, Nickell JR, Dwoskin LP, Zhan CG, Liu C, Tsodikov OV, Rangnekar VM, Watt DS (2016) Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin. Org Biomol Chem 14:74–84CrossRefGoogle Scholar
  3. 3.
    Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob RJ, Crist SA, Humphreys S, Rangnekar VM (1994) Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ 5:457–466PubMedGoogle Scholar
  4. 4.
    Chakraborty M, Qiu SG, Vasudevan KM, Rangnekar VM (2001) Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression. Can Res 61:7255–7263Google Scholar
  5. 5.
    Burikhanov R, Zhao Y, Goswami A, Qiu S, Schwarze SR, Rangnekar VM (2009) The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 138:377–388CrossRefGoogle Scholar
  6. 6.
    Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27:6434–6451CrossRefGoogle Scholar
  7. 7.
    Guicciardi ME, Leist M, Gores GJ (2004) Lysosomes in cell death. Oncogene 23:2881–2890CrossRefGoogle Scholar
  8. 8.
    Dielschneider RF, Henson ES, Gibson SB (2017) Lysosomes as oxidative targets for cancer therapy. Oxid Med Cell Longev 2017:3749157CrossRefGoogle Scholar
  9. 9.
    Seo SU, Kim TH, Kim DE, Min KJ, Kwon TK (2017) NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. Redox Biol 13:608–622CrossRefGoogle Scholar
  10. 10.
    Lee GH, Jin SW, Kim SJ, Pham TH, Choi JH, Jeong HG (2019) Tetrabromobisphenol A induces MMP-9 expression via NADPH oxidase and the activation of ROS, MAPK, and Akt pathways in human breast cancer MCF-7 cells. Toxicol Res 35:93–101CrossRefGoogle Scholar
  11. 11.
    Zeng XC, Bhasin S, Wu X, Lee JG, Maffi S, Nichols CJ, Lee KJ, Taylor JP, Greene LE, Eisenberg E (2004) Hsp70 dynamics in vivo: effect of heat shock and protein aggregation. J Cell Sci 117:4991–5000CrossRefGoogle Scholar
  12. 12.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446CrossRefGoogle Scholar
  13. 13.
    Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zuniga-Pflucker JC, Kroemer G, Penninger JM (2001) Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410:549–554CrossRefGoogle Scholar
  14. 14.
    Sperandio S, de Belle I, Bredesen DE (2000) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 97:14376–14381CrossRefGoogle Scholar
  15. 15.
    Sperandio S, Poksay K, de Belle I, Lafuente MJ, Liu B, Nasir J, Bredesen DE (2004) Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ 11:1066–1075CrossRefGoogle Scholar
  16. 16.
    Aits S, Jaattela M (2013) Lysosomal cell death at a glance. J Cell Sci 126:1905–1912CrossRefGoogle Scholar
  17. 17.
    Nylandsted J, Gyrd-Hansen M, Danielewicz A, Fehrenbacher N, Lademann U, Hoyer-Hansen M, Weber E, Multhoff G, Rohde M, Jaattela M (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200:425–435CrossRefGoogle Scholar
  18. 18.
    Nalca A, Qiu SG, El-Guendy N, Krishnan S, Rangnekar VM (1999) Oncogenic Ras sensitizes cells to apoptosis by Par-4. J Biol Chem 274:29976–29983CrossRefGoogle Scholar

Copyright information

© Korean Society of Toxicology 2019

Authors and Affiliations

  • Kyoung-jin Min
    • 1
  • Sk Abrar Shahriyar
    • 1
  • Taeg Kyu Kwon
    • 1
    Email author
  1. 1.Department of Immunology, School of MedicineKeimyung UniversityDaeguSouth Korea

Personalised recommendations