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The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis

  • Original Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND

Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis.

METHODS

Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining.

RESULTS

At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells.

CONCLUSION

The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.

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References

  1. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11:88.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Sun Y, Zheng Y, Wang C, Liu Y. Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis. 2018;9:753.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.

    Article  CAS  PubMed  Google Scholar 

  5. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447:864–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76.

    Article  CAS  PubMed  Google Scholar 

  7. Casale G, Bonora C, Migliavacca A, Zurita IE, de Nicola P. Serum ferritin and ageing. Age Ageing. 1981;10:119–22.

    Article  CAS  PubMed  Google Scholar 

  8. Kadoglou NPE, Biddulph JP, Rafnsson SB, Trivella M, Nihoyannopoulos P, Demakakos P. The association of ferritin with cardiovascular and all-cause mortality in community-dwellers: The English longitudinal study of ageing. PLoS One. 2017;12:e0178994.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Louandre C, Marcq I, Bouhlal H, Lachaier E, Godin C, Saidak Z, et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett. 2015;356:971–7.

    Article  CAS  PubMed  Google Scholar 

  10. Hanson LR, Roeytenberg A, Martinez PM, Coppes VG, Sweet DC, Rao RJ, et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Ther. 2009;330:679–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Lin X, Ping J, Wen Y, Wu Y. The mechanism of ferroptosis and applications in tumor treatment. Front Pharmacol. 2020;11:1061.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Sun X, Niu X, Chen R, He W, Chen D, Kang R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016;64:488–500.

    Article  CAS  PubMed  Google Scholar 

  14. Wang SF, Chen MS, Chou YC, Ueng YF, Yin PH, Yeh TS, et al. Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2alpha-ATF4-xCT pathway. Oncotarget. 2016;7:74132–51.

    Article  PubMed Central  PubMed  Google Scholar 

  15. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Jeon OH, David N, Campisi J, Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. J Clin Invest. 2018;128:1229–37.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Boccardi V, Pelini L, Ercolani S, Ruggiero C, Mecocci P. From cellular senescence to Alzheimer’s disease: The role of telomere shortening. Ageing Res Rev. 2015;22:1–8.

    Article  CAS  PubMed  Google Scholar 

  18. Aguayo-Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, et al. Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 2019;30:129–42.e4.

  19. Lucke-Wold BP, Logsdon AF, Turner RC, Rosen CL, Huber JD. Aging, the metabolic syndrome, and ischemic stroke: redefining the approach for studying the blood-brain barrier in a complex neurological disease. Adv Pharmacol. 2014;71:411–49.

    Article  CAS  PubMed  Google Scholar 

  20. Shimizu I, Minamino T. Cellular senescence in cardiac diseases. J Cardiol. 2019;74:313–9.

    Article  PubMed  Google Scholar 

  21. Gorenne I, Kavurma M, Scott S, Bennett M. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc Res. 2006;72:9��17.

    Article  CAS  PubMed  Google Scholar 

  22. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134:657–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Papadopoulos D, Magliozzi R, Mitsikostas DD, Gorgoulis VG, Nicholas RS. Aging, cellular senescence, and progressive multiple sclerosis. Front Cell Neurosci. 2020;14:178.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Park JS, Piao J, Park G, Yoo KS, Hong HS. Osteoporotic conditions influence the activity of adipose-derived stem cells. Tissue Eng Regen Med. 2020;17:875–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim YY, Kim YJ, Kim H, Kang BC, Ku SY, Suh CS. Modulatory effects of single and complex vitamins on the in vitro growth of Murine Ovarian Follicles. Tissue Eng Regen Med. 2019;16:275–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol. 2020;16:263–75.

    Article  CAS  PubMed  Google Scholar 

  27. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.

    Article  CAS  PubMed  Google Scholar 

  28. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288:518–36.

    Article  CAS  PubMed  Google Scholar 

  29. Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23:775–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019;22:719–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15:973–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Walaszczyk A, Dookun E, Redgrave R, Tual-Chalot S, Victorelli S, Spyridopoulos I, et al. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging Cell. 2019;18:e12945.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Oost W, Talma N, Meilof JF, Laman JD. Targeting senescence to delay progression of multiple sclerosis. J Mol Med (Berl). 2018;96:1153–66.

    Article  CAS  Google Scholar 

  34. Masaldan S, Clatworthy SAS, Gamell C, Meggyesy PM, Rigopoulos AT, Haupt S, et al. Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol. 2018;14:100–15.

    Article  CAS  PubMed  Google Scholar 

  35. Sui S, Zhang J, Xu S, Wang Q, Wang P, Pang D. Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells. Cell Death Dis. 2019;10:331.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Wakita M, Takahashi A, Sano O, Loo TM, Imai Y, Narukawa M, et al. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat Commun. 2020;11:1935.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Aoshiba K, Tsuji T, Nagai A. Bleomycin induces cellular senescence in alveolar epithelial cells. Eur Respir J. 2003;22:436–43.

    Article  CAS  PubMed  Google Scholar 

  38. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016;15:428–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016;22:78–83.

    Article  CAS  PubMed  Google Scholar 

  40. Kang R, Kroemer G, Tang D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. 2019;133:162–8.

    Article  CAS  PubMed  Google Scholar 

  41. Killilea DW, Wong SL, Cahaya HS, Atamna H, Ames BN. Iron accumulation during cellular senescence. Ann N Y Acad Sci. 2004;1019:365–7.

    Article  CAS  PubMed  Google Scholar 

  42. Wang B, Kohli J, Demaria M. Senescent cells in cancer therapy: Friends or Foes? Trends Cancer. 2020;6:838–57.

    Article  CAS  PubMed  Google Scholar 

  43. Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ. 1998;5:551–62.

    Article  CAS  PubMed  Google Scholar 

  44. Harel-Adar T, Ben Mordechai T, Amsalem Y, Feinberg MS, Leor J, Cohen S. Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair. Proc Natl Acad Sci U S A. 2011;108:1827–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Rodriguez-Fernandez S, Pujol-Autonell I, Brianso F, Perna-Barrull D, Cano-Sarabia M, Garcia-Jimeno S, et al. Phosphatidylserine-Liposomes promote tolerogenic features on dendritic cells in Human Type 1 Diabetes by apoptotic mimicry. Front Immunol. 2018;9:253.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Handa P, Thomas S, Morgan-Stevenson V, Maliken BD, Gochanour E, Boukhar S, et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J Leukoc Biol. 2019;105:1015–26.

    Article  CAS  PubMed  Google Scholar 

  47. Gan ZS, Wang QQ, Li JH, Wang XL, Wang YZ, Du HH. Iron Reduces M1 macrophage polarization in RAW264.7 Macrophages associated with inhibition of STAT1. Mediators Inflamm. 2017;2017:8570818.

  48. Agoro R, Taleb M, Quesniaux VFJ, Mura C. Cell iron status influences macrophage polarization. PLoS One. 2018;13:e0196921.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Kamei N, Adachi N, Ochi M. Magnetic cell delivery for the regeneration of musculoskeletal and neural tissues. Regen Ther. 2018;9:116–9.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Lee JR, Park BW, Kim J, Choo YW, Kim HY, Yoon JK, et al. Nanovesicles derived from iron oxide nanoparticles-incorporated mesenchymal stem cells for cardiac repair. Sci Adv. 2020;6:eaaz0952.

  51. Sensenig R, Sapir Y, MacDonald C, Cohen S, Polyak B. Magnetic nanoparticle-based approaches to locally target therapy and enhance tissue regeneration in vivo. Nanomedicine (Lond). 2012;7:1425–42.

    Article  CAS  Google Scholar 

  52. Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, et al. Programmed cell senescence during mammalian embryonic development. Cell. 2013;155:1104–18.

    Article  CAS  PubMed  Google Scholar 

  53. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31:722–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgement

This study was supported by the National Research Foundation of Korea (2017R1A2B3005842 and 2019M3A9H1103651).

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Authors and Affiliations

  1. Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea

    Seokhyeong Go, Mikyung Kang & Byung‐Soo Kim

  2. School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea

    Sung Pil Kwon, Mungyo Jung & Byung‐Soo Kim

  3. Department of Biomedical Sciences, BK21 Graduate Program, Korea University of College of Medicine, Seoul, 02841, Republic of Korea

    Ok Hee Jeon

  4. Institute of Chemical Processes, Institute of Engineering Research, and BioMAX, Seoul National University, Seoul, 08826, Republic of Korea

    Byung‐Soo Kim

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  1. Seokhyeong Go
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Correspondence to Ok Hee Jeon or Byung‐Soo Kim.

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Go, S., Kang, M., Kwon, S.P. et al. The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis. Tissue Eng Regen Med 18, 841–850 (2021). https://doi.org/10.1007/s13770-021-00346-z

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