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Sesamin induces A549 cell mitophagy and mitochondrial apoptosis via a reactive oxygen species-mediated reduction in mitochondrial membrane potential

  • Yang, Shasha (Center of Morphological Experiment, Medical College of Yanbian University) ;
  • Li, Xiangdan (Center of Morphological Experiment, Medical College of Yanbian University) ;
  • Dou, Haowen (Center of Morphological Experiment, Medical College of Yanbian University) ;
  • Hu, Yulai (Center of Morphological Experiment, Medical College of Yanbian University) ;
  • Che, Chengri (Department of Thoracic Surgery, Affiliated Hospital of Yanbian University) ;
  • Xu, Dongyuan (Center of Morphological Experiment, Medical College of Yanbian University)
  • Received : 2019.10.27
  • Accepted : 2020.02.28
  • Published : 2020.05.01

Abstract

Sesamin, a lipid-soluble lignin originally isolated from sesame seeds, which induces cancer cell apoptosis and autophagy. In the present study, has been reported that sesamin induces apoptosis via several pathways in human lung cancer cells. However, whether mitophagy is involved in sesamin induced lung cancer cell apotosis remains unclear. This study, the anticancer activity of sesamin in lung cancer was studied by reactive oxygen species (ROS) and mitophagy. A549 cells were treated with sesamin, and cell viability, migration ability, and cell cycle were assessed using the CCK8 assay, scratch-wound test, and flow cytometry, respectively. ROS levels, mitochondrial membrane potential, and apoptosis were examined by flow cytometric detection of DCFH-DA fluorescence and by using JC-1 and TUNEL assays. The results indicated that sesamin treatment inhibited the cell viability and migration ability of A549 cells and induced G0/G1 phase arrest. Furthermore, sesamin induced an increase in ROS levels, a reduction in mitochondrial membrane potential, and apoptosis accompanied by an increase in cleaved caspase-3 and cleaved caspase-9. Additionally, sesamin triggered mitophagy and increased the expression of PINK1 and translocation of Parkin from the cytoplasm to the mitochondria. However, the antioxidant N-acetyl-L-cysteine clearly reduced the oxidative stress and mitophagy induced by sesamin. Furthermore, we found that cyclosporine A (an inhibitor of mitophagy) decreased the inhibitory effect of sesamin on A549 cell viability. Collectively, our data indicate that sesamin exerts lethal effects on lung cancer cells through the induction of ROS-mediated mitophagy and mitochondrial apoptosis.

Keywords

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-2917. https://doi.org/10.1002/ijc.25516
  2. Wakelee H, Kelly K, Edelman MJ. 50 Years of progress in the systemic therapy of non-small cell lung cancer. Am Soc Clin Oncol Educ Book. 2014:177-189.
  3. Majdalawieh AF, Massri M, Nasrallah GK. A comprehensive review on the anti-cancer properties and mechanisms of action of sesamin, a lignan in sesame seeds (Sesamum indicum). Eur J Pharmacol. 2017;815:512-521. https://doi.org/10.1016/j.ejphar.2017.10.020
  4. Xu P, Cai F, Liu X, Guo L. Sesamin inhibits lipopolysaccharideinduced proliferation and invasion through the p38-MAPK and NF-${\kappa}B$ signaling pathways in prostate cancer cells. Oncol Rep. 2015;33:3117-3123. https://doi.org/10.3892/or.2015.3888
  5. Siao AC, Hou CW, Kao YH, Jeng KC. Effect of sesamin on apoptosis and cell cycle arrest in human breast cancer mcf-7 cells. Asian Pac J Cancer Prev. 2015;16:3779-3783. https://doi.org/10.7314/APJCP.2015.16.9.3779
  6. Dou H, Yang S, Hu Y, Xu D, Liu L, Li X. Sesamin induces ER stressmediated apoptosis and activates autophagy in cervical cancer cells. Life Sci. 2018;200:87-93. https://doi.org/10.1016/j.lfs.2018.03.003
  7. Wang HM, Cheng KC, Lin CJ, Hsu SW, Fang WC, Hsu TF, Chiu CC, Chang HW, Hsu CH, Lee AY. Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints. Cancer Sci. 2010;101:2612-2620. https://doi.org/10.1111/j.1349-7006.2010.01701.x
  8. Fang Q, Zhu Y, Wang Q, Song M, Gao G, Zhou Z. Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt-PI3K signaling pathway in lung cancer cells. Int J Mol Med. 2019;43:507-516.
  9. Chen Y, Li H, Zhang W, Qi W, Lu C, Huang H, Yang Z, Liu B, Zhang L. Sesamin suppresses NSCLC cell proliferation and induces apoptosis via Akt/p53 pathway. Toxicol Appl Pharmacol. 2020;387:114848. https://doi.org/10.1016/j.taap.2019.114848
  10. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 1979;59:527-605. https://doi.org/10.1152/physrev.1979.59.3.527
  11. Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993;264(4 Pt 1):C961-C967. https://doi.org/10.1152/ajpcell.1993.264.4.C961
  12. Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005;8:3-5. https://doi.org/10.1089/rej.2005.8.3
  13. Xiao B, Deng X, Lim GGY, Zhou W, Saw WT, Zhou ZD, Lim KL, Tan EK. p62-Mediated mitochondrial clustering attenuates apoptosis induced by mitochondrial depolarization. Biochim Biophys Acta Mol Cell Res. 2017;1864:1308-1317. https://doi.org/10.1016/j.bbamcr.2017.04.009
  14. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010;189:211-221. https://doi.org/10.1083/jcb.200910140
  15. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795-803. https://doi.org/10.1083/jcb.200809125
  16. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8:e1000298. https://doi.org/10.1371/journal.pbio.1000298
  17. Halestrap AP, Connern CP, Griffiths EJ, Kerr PM. Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol Cell Biochem. 1997;174:167-172. https://doi.org/10.1023/A:1006879618176
  18. Akl MR, Ayoub NM, Abuasal BS, Kaddoumi A, Sylvester PW. Sesamin synergistically potentiates the anticancer effects of $\gamma$-tocotrienol in mammary cancer cell lines. Fitoterapia. 2013;84:347-359. https://doi.org/10.1016/j.fitote.2012.12.013
  19. Li L, Tan J, Miao Y, Lei P, Zhang Q. ROS and autophagy: interactions and molecular regulatory mechanisms. Cell Mol Neurobiol. 2015;35:615-621. https://doi.org/10.1007/s10571-015-0166-x
  20. Yang Y, Karakhanova S, Hartwig W, D'Haese JG, Philippov PP, Werner J, Bazhin AV. Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J Cell Physiol. 2016;231:2570-2581. https://doi.org/10.1002/jcp.25349
  21. Kang D, Hamasaki N. Mitochondrial oxidative stress and mitochondrial DNA. Clin Chem Lab Med. 2003;41:1281-1288. https://doi.org/10.1515/CCLM.2003.195
  22. Zhang B, Bian W, Pal A, He Y. Macrophage apoptosis induced by aqueous C60 aggregates changing the mitochondrial membrane potential. Environ Toxicol Pharmacol. 2015;39:237-246. https://doi.org/10.1016/j.etap.2014.11.013
  23. Vagner T, Mouravlev A, Young D. A novel bicistronic sensor vector for detecting caspase-3 activation. J Pharmacol Toxicol Methods. 2015;72:11-18. https://doi.org/10.1016/j.vascn.2014.11.006
  24. Farias-de-Oliveira DA, Villa-Verde DM, Nunes Panzenhagen PH, Silva dos Santos D, Berbert LR, Savino W, de Meis J. Caspase-8 and caspase-9 mediate thymocyte apoptosis in Trypanosoma cruzi acutely infected mice. J Leukoc Biol. 2013;93:227-234. https://doi.org/10.1189/jlb.1211589
  25. Martinez-Fabregas J, Diaz-Moreno I, Gonzalez-Arzola K, Janocha S, Navarro JA, Hervas M, Bernhardt R, Velazquez-Campoy A, Diaz-Quintana A, De la Rosa MA. Structural and functional analysis of novel human cytochrome C targets in apoptosis. Mol Cell Proteomics. 2014;13:1439-1456. https://doi.org/10.1074/mcp.M113.034322
  26. Li J, Wu DD, Zhang JX, Wang J, Ma JJ, Hu X, Dong WG. Mitochondrial pathway mediated by reactive oxygen species involvement in $\alpha$-hederin-induced apoptosis in hepatocellular carcinoma cells. World J Gastroenterol. 2018;24:1901-1910. https://doi.org/10.3748/wjg.v24.i17.1901
  27. Laulier C, Lopez BS. The secret life of Bcl-2: apoptosis-independent inhibition of DNA repair by Bcl-2 family members. Mutat Res. 2012;751:247-257. https://doi.org/10.1016/j.mrrev.2012.05.002
  28. Chen Q, Lesnefsky EJ. Blockade of electron transport during ischemia preserves bcl-2 and inhibits opening of the mitochondrial permeability transition pore. FEBS Lett. 2011;585:921-926. https://doi.org/10.1016/j.febslet.2011.02.029
  29. Pan LL, Wang AY, Huang YQ, Luo Y, Ling M. Mangiferin induces apoptosis by regulating Bcl-2 and Bax expression in the CNE2 nasopharyngeal carcinoma cell line. Asian Pac J Cancer Prev. 2014;15:7065-7068. https://doi.org/10.7314/APJCP.2014.15.17.7065
  30. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9-14. https://doi.org/10.1038/nrm3028
  31. Bertolin G, Ferrando-Miguel R, Jacoupy M, Traver S, Grenier K, Greene AW, Dauphin A, Waharte F, Bayot A, Salamero J, Lombes A, Bulteau AL, Fon EA, Brice A, Corti O. The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance. Autophagy. 2013;9:1801-1817. https://doi.org/10.4161/auto.25884
  32. Jin SM, Youle RJ. PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci. 2012;125(Pt 4):795-799. https://doi.org/10.1242/jcs.093849
  33. Altshuler-Keylin S, Shinoda K, Hasegawa Y, Ikeda K, Hong H, Kang Q, Yang Y, Perera RM, Debnath J, Kajimura S. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 2016;24:402-419. https://doi.org/10.1016/j.cmet.2016.08.002
  34. Kimura T, Takabatake Y, Takahashi A, Isaka Y. Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res. 2013;73:3-7. https://doi.org/10.1158/0008-5472.CAN-12-2464
  35. Kim JS, He L, Lemasters JJ. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun. 2003;304:463-470. https://doi.org/10.1016/S0006-291X(03)00618-1
  36. Kim JS, Qian T, Lemasters JJ. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes. Gastroenterology. 2003;124:494-503. https://doi.org/10.1053/gast.2003.50059

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