Advertisement

Tumor Biology

, Volume 35, Issue 10, pp 10159–10167 | Cite as

Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7

  • Kandasamy Palanivel
  • Veerasamy Kanimozhi
  • Balamuthu Kadalmani
Research Article

Abstract

Verrucarin A (VA), an active constituent of pathogenic fungus Myrothecium verrucaria, which has the ability to inhibit the growth of breast cancer cells. However, the mechanism by which VA exerts its inhibitory potential remains elusive. Here, we demonstrated that VA inhibited the growth of MCF-7 breast cancer cells, increased the levels of reactive oxygen species (ROS), and subsequently induced mitochondrial membrane potential (Δψm) loss, leading to the increase of Bax/Bcl-2 ratio, cytochrome c release, caspase activation, PARP degradation, and apoptosis. VA effectively increased the phosphorylation of p38MAPK and diminished the phosphorylation of ERK/Akt. In addition, VA caused cell cycle deregulation through the induction of p21 and p53. Furthermore, ROS scavenger (n-acetyl-l-cysteine) and p38MAPK inhibitor (SB202190) effectively abrogated the VA-induced cell cycle deregulation and apoptosis. Conversely, U0126, an ERK1/2 inhibitor, enhanced the VA-induced apoptotic signals. Taken together, our results suggest that VA-induces apoptosis and cell cycle deregulation in MCF-7 cells through ROS-dependent p38MAPK activation.

Keywords

Apoptosis Cancer Cell cycle deregulation MAPK ROS Verrucarin A 

Notes

Acknowledgments

This study was supported by University Grants Commission, India, under the Special Assistance Programme (UGC–SAP)-Research Fellowship for Meritorious Students in Science (RFMS).

Conflicts of interest

None

References

  1. 1.
    Chin L, Gray JW. Translating insights from the cancer genome into clinical practice. Nature. 2008;452:553–63.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Molinari M. Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 2000;33:261–74.CrossRefPubMedGoogle Scholar
  3. 3.
    Andersen B, Nielsen KF, Jarvis BB. Characterization of Stachybotrys from water-damaged buildings based on morphology, growth, and metabolite production. Mycologia. 2002;94:392–403.CrossRefPubMedGoogle Scholar
  4. 4.
    Oda T, Namikoshi M, Akano K, Kobayashi H, Honma Y, Kasahara T. Verrucarin A inhibition of MAP kinase activation in a PMA-stimulated promyelocytic leukemia cell line. Mar Drugs. 2005;3:64–73.PubMedCentralCrossRefGoogle Scholar
  5. 5.
    Palanivel K, Kanimozhi V, Kadalmani B, Akbarsha MA. Verrucarin A, a protein synthesis inhibitor, induces growth inhibition and apoptosis in breast cancer cell lines MDA-MB-231 and T47D. Biotechnol Lett. 2013;35:1395–403.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen YW, Huang CF, Yang CY, Yen CC, Tsai KS, Liu SH. Inorganic mercury causes pancreatic beta-cell death via the oxidative stress induced apoptotic and necrotic pathways. Toxicol Appl Pharmacol. 2010;243:323–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Son YO, Hitron JA, Wang X, Chang QS, Pan JJ, Zhang Z, et al. Cr (VI) induces mitochondrial-mediated and caspase-dependent apoptosis through reactive oxygen species-mediated p53 activation in JB6 Cl41 cells. Toxicol Appl Pharmacol. 2010;245:226–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Marsden VS, O'Connor L, O'Reilly LA, Silke J, Metcalf D, Ekert PG. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature. 2002;19:634–7.CrossRefGoogle Scholar
  9. 9.
    Verma YK, Gangenahalli GU, Singh VK, Gupta P, Chandra R, Sharma RK, et al. Cell death regulation by B-cell lymphoma protein. Apoptosis. 2006;11:459–71.CrossRefPubMedGoogle Scholar
  10. 10.
    Roy AM, Baliga MS, Elmets CA, Katiyar KS. Grape seed proanthocyanidins induce apoptosis through p53, Bax and caspase-3 pathways. Neoplasia. 2005;7:24–36.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Du H, Wolf J, Schafer B, Moldoveanu T, Chipuk JE, Kuwana T. BH3 domains other than Bim and Bid can directly activate Bax/Bak. J Biol Chem. 2011;286:491–501.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Suen DF, Norris KL, Youle RK. Mitochondrial dynamics and apoptosis. Genes Dev. 2008;22:1577–90.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Carvalho H, Evelson P, Sigaud S, Gonzalez-Flecha B. Mitogen-activated protein kinases modulate H(2)O(2)-induced apoptosis in primary rat alveolar epithelial cells. J Cell Biochem. 2004;92:502–13.CrossRefPubMedGoogle Scholar
  14. 14.
    Jung E, Byun S, Kim S, Kim M, Park D, Lee J. Isomenthone protects human dermal fibroblasts from TNF-alpha-induced death possibly by preventing activation of JNK and p38 MAPK. Food Chem Toxicol. 2012;50:3514–20.CrossRefPubMedGoogle Scholar
  15. 15.
    Park DH, De Xu H, Shim J, Li YC, Lee JH, Cho SC, et al. Stephania delavayi Diels. inhibits breast carcinoma proliferation through the p38MAPK/NF-kappa B/COX-2 pathway. Oncol Rep. 2011;26:833–41.PubMedGoogle Scholar
  16. 16.
    Valko M, Rhodes CJ, Moncol J, Zakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160:1–40.CrossRefPubMedGoogle Scholar
  17. 17.
    Tamura S, Hanada M, Ohnishi M, Katsura K, Sasaki M, Kobayashi T. Regulation of stress-activated protein kinase signaling pathways by protein phosphatases. Eur J Biochem. 2002;269:1060–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Cowan KJ, Storey KB. Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol. 2003;206:1107–15.CrossRefPubMedGoogle Scholar
  19. 19.
    Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M, Lord JM. Serine/threonine protein kinases and apoptosis. Exp Cell Res. 2000;256:34–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22:8983–98.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang X, Jin B, Huang C. The PI3K/Akt pathway and its downstream transcriptional factors as targets for chemoprevention. Curr Cancer Drug Targets. 2007;7:305–16.CrossRefPubMedGoogle Scholar
  22. 22.
    Trisciuoglio D, Iervolino A, Zupi G, DelBufalo D. Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol Biol Cell. 2005;16:4153–62.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Jiang C, Wang Z, Ganther H, Lu J. Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells. Mol Cancer Ther. 2002;1:1059–66.PubMedGoogle Scholar
  24. 24.
    Ho A, Dowdy SF. Regulation of G (1) cell-cycle progression by oncogenes and tumor suppressor genes. Curr Opin Genet Dev. 2002;12:47–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Fulda S, Meyer E, Friesen C, Susin SA, Kroemer G, Debatin M. Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene. 2001;20:1063–75.CrossRefPubMedGoogle Scholar
  27. 27.
    Winters ZE, Lee KRD, Bradburn MJ, Norbury CJ, Harris AL. Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/neu in breast cancer and is an independent predictor of prognosis. Breast Cancer Res. 2003;5:242–9.CrossRefGoogle Scholar
  28. 28.
    Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993;366:701–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Mailand N, Gibbs-Seymour I, Bekker-Jensen S. Regulation of PCNA protein interactions for genome stability. Nat Rev Mol Cell Biol. 2013;14:269–82.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Kandasamy Palanivel
    • 1
  • Veerasamy Kanimozhi
    • 1
  • Balamuthu Kadalmani
    • 1
  1. 1.Department of Animal ScienceBharathidasan UniversityTiruchirappalliIndia

Personalised recommendations