Skip to main content

Advertisement

Log in

Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Luteolin, a common dietary flavonoid, induces apoptosis of many types of cancer cells. However, its role in glioblastoma and the potential mechanisms remain unknown. In this research, we studied the molecular mechanisms of the anti-cancer effect of luteolin in glioblastoma cancer cell lines.

Methods

Both U251MG and U87MG human glioblastoma cell lines were tested. Cell growth was assessed by the cell counting kit-8. Cell apoptosis was detected with flow cytometry and caspase-3 immunofluorescence staining. The protein levels of caspase-3/Bax/Bcl-2 and p-PERK/p-eIF2α/ATF4/CHOP/caspase-12 pathway were analyzed using western blots. Reactive oxygen species generation was measured with DCFH-DA staining using flow cytometry. Mitochondrial membrane potential was tested with JC-1 staining. Anti-cancer effect in vivo was measured using tumor xenograft mode in nude mice.

Results

Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels. Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12. Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis. What’s more, we also showed the anticancer effect of luteolin in vivo.

Conclusions

Our results suggest that luteolin induces apoptosis through activating ER stress and mitochondrial dysfunction in glioblastoma cell lines and in vivo, which provides the anti-cancer candidate to treat glioblstoma.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  CAS  PubMed  Google Scholar 

  2. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591

    Article  CAS  PubMed  Google Scholar 

  3. Yang J, Lu M, Lee C, Chen G, Lin Y, Chang F et al (2011) Selective targeting of breast cancer cells through ROS-mediated mechanisms potentiates the lethality of paclitaxel by a novel diterpene, gelomulide K. Free Radic Biol Med 51:641–657

    Article  CAS  PubMed  Google Scholar 

  4. Nogueira V, Hay N (2013) Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res 19:4309–4314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ghobrial IM, Witzig TE, Adjei AA (2005) Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 55:178–194

    Article  PubMed  Google Scholar 

  6. Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13:184–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Choi AY, Choi JH, Yoon H, Hwang K, Noh MH, Choe W et al (2011) Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. Eur J Pharmacol 668:115–126

    Article  CAS  PubMed  Google Scholar 

  8. Neuhouser ML (2004) Dietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer 50:1–7

    Article  CAS  PubMed  Google Scholar 

  9. Mencherini T, Picerno P, Scesa C, Aquino R (2007) Triterpene, antioxidant, and antimicrobial compounds from Melissaofficinalis. J Nat Prod 70:1889–1894

    Article  CAS  PubMed  Google Scholar 

  10. Lin Y, Shi R, Wang X, Shen HM (2008) Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 8:634–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai X, Ye T, Liu C, Lu W, Lu M, Zhang J et al (2011) Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol In Vitro 25:1385–1391

    Article  CAS  PubMed  Google Scholar 

  12. Wu B, Zhang Q, Shen W, Zhu J (2008) Anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cell line. Mol Cell Biochem 313:125–132

    Article  CAS  PubMed  Google Scholar 

  13. Chian S, Thapa R, Chi Z, Wang XJ, Tang X (2014) Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Co 447:602–608

    Article  Google Scholar 

  14. Nakagawa S, Deli MA, Kawaguchi H, Shimizudani T, Shimono T, Kittel A et al (2009) A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 54:253–263

    Article  CAS  PubMed  Google Scholar 

  15. Zou P, Zhang J, Xia Y, Kanchana K, Guo G, Chen W et al (2015) ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer. Oncotarget 6:5860–5876

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang L, Wang H, Ding K, Xu J (2015) FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells. Toxicol Lett 236:43–59

    Article  CAS  PubMed  Google Scholar 

  17. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hotamisligil GKS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  CAS  PubMed  Google Scholar 

  20. Desagher S, Martinou J (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10:369–377

    Article  CAS  PubMed  Google Scholar 

  21. Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746

    Article  CAS  PubMed  Google Scholar 

  22. Das A, Banik NL, Ray SK (2010) Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes. Cancer Am Cancer Soc 116:164–176

    CAS  Google Scholar 

  23. Selvendiran K (2006) Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. Cancer Res 66:4826–4834

    Article  CAS  PubMed  Google Scholar 

  24. Shi RX, Ong CN, Shen HM (2004) Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. Oncogene 23:7712–7721

    Article  CAS  PubMed  Google Scholar 

  25. Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794–798

    CAS  PubMed  Google Scholar 

  26. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947

    Article  CAS  PubMed  Google Scholar 

  27. Bragado P, Armesilla A, Silva A, Porras A (2007) Apoptosis by cisplatin requires p53 mediated p38α MAPK activation through ROS generation. Apoptosis 12:1733–1742

    Article  CAS  PubMed  Google Scholar 

  28. Alexandre J, Hu Y, Lu W, Pelicano H, Huang P(2007) Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 67:3512–3517

    Article  CAS  PubMed  Google Scholar 

  29. Rao R, Nalluri S, Fiskus W, Savoie A, Buckley KM, Ha K, et al (2010) Role of CAAT/enhancer binding protein homologous protein in Panobinostat-mediated potentiation of Bortezomib-induced lethal endoplasmic reticulum stress in mantle cell lymphoma cells. Clin Cancer Res 16:4742–4754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Oakes SA (2017) Endoplasmic reticulum proteostasis: a key checkpoint in cancer. Am J Physiol Cell Physiol 312:C93–C102

    Article  PubMed  Google Scholar 

  31. Kim AD, Madduma HS, Piao MJ, Kang KA, Cho SJ, Hyun JW (2015) Esculetin induces apoptosis in human colon cancer cells by inducing endoplasmic reticulum stress. Cell Biochem Funct 33:487–494

    Article  CAS  PubMed  Google Scholar 

  32. Boyce M, Yuan J (2006) Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ 13:363–373

    Article  CAS  PubMed  Google Scholar 

  33. Ge W, Yin Q, Xian H (2015) Wogonin induced mitochondrial dysfunction and endoplasmic reticulum stress in human malignant neuroblastoma cells via IRE1alpha-dependent pathway. J Mol Neurosci 56:652–662

    Article  CAS  PubMed  Google Scholar 

  34. Wu CT, Weng TI, Chen LP, Chiang CK, Liu SH (2013) Involvement of caspase-12-dependent apoptotic pathway in ionic radiocontrast urografin-induced renal tubular cell injury. Toxicol Appl Pharmacol 266:167–175

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr Han Yanling for the technical assistance. This work was supported by Grants from the National Natural Science Foundation of China (No. 81371357) and China Postdoctoral Science Foundation funded project under Grant (No. 2014M562665).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Handong Wang.

Ethics declarations

Conflict of interest

The authors disclose no potential conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Wang, H., Jia, Y. et al. Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma. Cancer Chemother Pharmacol 79, 1031–1041 (2017). https://doi.org/10.1007/s00280-017-3299-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3299-4

Keywords

Navigation