Skip to main content
SpringerLink
Log in

Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Gasdermin E (GSDME) has an important role in inducing secondary necrosis/pyroptosis. Upon apoptotic stimulation, it can be cleaved by activated caspase-3 to generate its N-terminal fragment (GSDME-NT), which executes pyroptosis by perforating the plasma membrane. GSDME is expressed in many human lung cancers including A549 cells. Paclitaxel and cisplatin are two representative chemotherapeutic agents for lung cancers, which induce apoptosis via different action mechanisms. However, it remains unclear whether they can induce GSDME-mediated secondary necrosis/pyroptosis in lung A549 cancer cells. Here we showed that both paclitaxel and cisplatin evidently induced apoptosis in A549 cells as revealed by the activation of multiple apoptotic markers. Notably, some of the dying cells displayed characteristic morphology of secondary necrosis/pyroptosis, by blowing large bubbles from the cellular membrane accompanied by caspase-3 activation and GSDME-NT generation. But the ability of cisplatin to induce this phenomenon was much stronger than that of paclitaxel. Consistent with this, cisplatin triggered much higher activation of caspase-3 and generation of GSDME-NT than paclitaxel, suggesting that the levels of secondary necrosis/pyroptosis correlated with the levels of active caspase-3 and GSDME-NT. Supporting this, caspase-3 specific inhibitor (Ac-DEVD-CHO) suppressed cisplatin-induced GSDME-NT generation and concurrently reduced the secondary necrosis/pyroptosis. Besides, GSDME knockdown significantly inhibited cisplatin- but not paclitaxel-induced secondary necrosis/pyroptosis. These results indicated that cisplatin induced higher levels of secondary necrosis/pyroptosis in A549 cells than paclitaxel, suggesting that cisplatin may provide additional advantages in the treatment of lung cancers with high levels of GSDME expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. https://doi.org/10.3322/caac.21254

    Article  PubMed  Google Scholar 

  3. Priyadarshini K, Keerthi AU (2012) Paclitaxel against cancer: a short review. Med Chem 2(7):139–141. https://doi.org/10.4172/2161-0444.1000130

    Article  CAS  Google Scholar 

  4. Fennell DA, Summers Y, Cadranel J, Benepal T, Christoph DC, Lal R, Das M, Maxwell F, Visseren-Grul C, Ferry D (2016) Cisplatin in the modern era: the backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat Rev 44:42–50. https://doi.org/10.1016/j.ctrv.2016.01.003

    Article  CAS  PubMed  Google Scholar 

  5. Arnal I, Wade RH (1995) How does taxol stabilize microtubules? Curr Biol 5(8):900–908. https://doi.org/10.1016/S0960-9822(95)00180-1

    Article  CAS  PubMed  Google Scholar 

  6. Piperno G, LeDizet M, Chang XJ (1987) Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. J Cell Biol 104(2):289–302. https://doi.org/10.1083/jcb.104.2.289

    Article  CAS  PubMed  Google Scholar 

  7. Ganguly A, Yang H, Cabral F (2013) Detection and quantification of microtubule detachment from centrosomes and spindle poles. Methods Cell Biol 115(20):49–62. https://doi.org/10.1016/B978-0-12-407757-7.00004-9

    Article  CAS  PubMed  Google Scholar 

  8. Florea AM, Busselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 3(1):1351–1371. https://doi.org/10.3390/cancers3011351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. https://doi.org/10.1016/j.ejphar.2014.07.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roos WP, Kaina B (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12(9):440–450. https://doi.org/10.1016/j.molmed.2006.07.007

    Article  CAS  PubMed  Google Scholar 

  11. Wang YP, Gao WQ, Shi XY, Ding JJ, Liu W, He HB, Wang K, Shao F (2017) Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547(7661):99–103. https://doi.org/10.1038/nature22393

    Article  CAS  PubMed  Google Scholar 

  12. Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES (2017) Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun 8:14128. https://doi.org/10.1038/ncomms14128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3(4):339–345. https://doi.org/10.1038/35070009

    Article  CAS  PubMed  Google Scholar 

  14. Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N (2014) Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014:150845. https://doi.org/10.1155/2014/150845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lu H, Zhang S, Wu J, Chen M, Cai MC, Fu Y, Li W, Wang J, Zhao X, Yu Z, Ma P, Zhuang G (2018) Molecular targeted therapies elicit concurrent apoptotic and GSDME-dependent pyroptotic tumor cell death. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-1478

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jian W, Bai Y, Li X, Kang J, Lei Y, Xue Y (2018) Phosphatidylethanolamine-binding protein 4 promotes the epithelial-to-mesenchymal transition in non-small cell lung cancer cells by activating the sonic hedgehog signaling pathway. J Cell Biochem https://doi.org/10.1002/jcb.27817

    Article  PubMed  Google Scholar 

  17. Py BF, Jin M, Desai BN, Penumaka A, Zhu H, Kober M, Dietrich A, Lipinski MM, Henry T, Clapham DE, Yuan J (2014) Caspase-11 controls interleukin-1beta release through degradation of TRPC1. Cell Rep 6(6):1122–1128. https://doi.org/10.1016/j.celrep.2014.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zha QB, Wei HX, Li CG, Liang YD, Xu LH, Bai WJ, Pan H, He XH, Ouyang DY (2016) ATP-induced inflammasome activation and pyroptosis is regulated by AMP-activated protein kinase in macrophages. Front Immunol 7:597. https://doi.org/10.3389/fimmu.2016.00597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xiang F, Wu R, Ni Z, Pan C, Zhan Y, Xu J, Meng X, Kang X (2014) MyD88 expression is associated with paclitaxel resistance in lung cancer A549 cells. Oncol Rep 32(5):1837–1844. https://doi.org/10.3892/or.2014.3433

    Article  CAS  PubMed  Google Scholar 

  20. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526(7575):660–665. https://doi.org/10.1038/nature15514

    Article  CAS  PubMed  Google Scholar 

  21. Baker PJ, Boucher D, Bierschenk D, Tebartz C, Whitney PG, D’Silva DB, Tanzer MC, Monteleone M, Robertson AA, Cooper MA, Alvarez-Diaz S, Herold MJ, Bedoui S, Schroder K, Masters SL (2015) NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. Eur J Immunol 45(10):2918–2926. https://doi.org/10.1002/eji.201545655

    Article  CAS  PubMed  Google Scholar 

  22. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526(7575):666–671. https://doi.org/10.1038/nature15541

    Article  CAS  PubMed  Google Scholar 

  23. Wang Y, Yin B, Li D, Wang G, Han X, Sun X (2018) GSDME mediates caspase-3-dependent pyroptosis in gastric cancer. Biochem Biophys Res Commun 495(1):1418–1425. https://doi.org/10.1016/j.bbrc.2017.11.156

    Article  CAS  PubMed  Google Scholar 

  24. Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256(1):42–49. https://doi.org/10.1006/excr.2000.4838

    Article  CAS  PubMed  Google Scholar 

  25. Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (∆ψm) in apoptosis; an update. Apoptosis 8(2):115–128. https://doi.org/10.1023/A:1022945107762

    Article  CAS  PubMed  Google Scholar 

  26. Byrd-Leifer CA, Block EF, Takeda K, Akira S, Ding A (2001) The role of MyD88 and TLR4 in the LPS-mimetic activity of taxol. Eur J Immunol 31(8):2448–2457. https://doi.org/10.1002/1521-4141(200108)31:8<2448::aid-immu2448>3.0.co;2-n

    Article  CAS  PubMed  Google Scholar 

  27. Masuda Y, Futamura M, Kamino H, Nakamura Y, Kitamura N, Ohnishi S, Miyamoto Y, Ichikawa H, Ohta T, Ohki M, Kiyono T, Egami H, Baba H, Arakawa H (2006) The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage. J Hum Genet 51(8):652–664. https://doi.org/10.1007/s10038-006-0004-6

    Article  CAS  PubMed  Google Scholar 

  28. Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, Van de Heyning P, McGuirt WT, Smith RJ, Willems PJ, Legan PK, Richardson GP, Van Camp G (1998) Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet 20(2):194–197. https://doi.org/10.1038/2503

    Article  PubMed  Google Scholar 

  29. de Beeck KO, Van Laer L, Van Camp G (2012) DFNA5, a gene involved in hearing loss and cancer: a review. Ann Otol Rhinol Laryngol 121(3):197–207. https://doi.org/10.1177/000348941212100310

    Article  PubMed  Google Scholar 

  30. Kim MS, Lebron C, Nagpal JK, Chae YK, Chang X, Huang Y, Chuang T, Yamashita K, Trink B, Ratovitski EA, Califano JA, Sidransky D (2008) Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer. Biochem Biophys Res Commun 370(1):38–43. https://doi.org/10.1016/j.bbrc.2008.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Akino K, Toyota M, Suzuki H, Imai T, Maruyama R, Kusano M, Nishikawa N, Watanabe Y, Sasaki Y, Abe T, Yamamoto E, Tarasawa I, Sonoda T, Mori M, Imai K, Shinomura Y, Tokino T (2007) Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer Sci 98(1):88–95. https://doi.org/10.1111/j.1349-7006.2006.00351.x

    Article  CAS  PubMed  Google Scholar 

  32. Kim MS, Chang X, Yamashita K, Nagpal JK, Baek JH, Wu G, Trink B, Ratovitski EA, Mori M, Sidransky D (2008) Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene 27(25):3624–3634. https://doi.org/10.1038/sj.onc.1211021

    Article  CAS  PubMed  Google Scholar 

  33. Ball B, Zeidan A, Gore SD, Prebet T (2017) Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings. Leuk Lymphoma 58(5):1022–1036. https://doi.org/10.1080/10428194.2016.1228927

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81873064, 81773965 and 81673664).

Author information

Author notes

  1. Cheng-cheng Zhang, Chen-guang Li and Yao-feng Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China

    Cheng-cheng Zhang, Chen-guang Li, Yao-feng Wang, Xian-hui He, Qiong-zhen Zeng, Chen-ying Zeng, Feng-yi Mai & Dong-yun Ouyang

  2. Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China

    Li-hui Xu

  3. Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou, China

    Bo Hu

Authors
  1. Cheng-cheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen-guang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yao-feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li-hui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xian-hui He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiong-zhen Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chen-ying Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Feng-yi Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dong-yun Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bo Hu or Dong-yun Ouyang.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2176 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Cc., Li, Cg., Wang, Yf. et al. Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis 24, 312–325 (2019). https://doi.org/10.1007/s10495-019-01515-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-019-01515-1

Keywords

Search

Navigation