Skip to main content
SpringerLink
Log in

Maclurin suppresses migration and invasion of human non-small-cell lung cancer cells via anti-oxidative activity and inhibition of the Src/FAK–ERK–β-catenin pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Recent reports indicated that ROS is closely related with cancer metastasis. ROS targets major signaling molecules which are known to be involved in migration and invasion of cancer cells. Here we report that maclurin, a major phenolic component of ethanol extracted mulberry twigs, exerts anti-metastatic effect in A549 human non-small-cell lung cancer cells. Maclurin suppresses intracellular ROS level in A549 human non-small-cell lung cancer cells. Also, maclurin down-regulates Src and ERK, which are well known to be regulated with redox state. Suppressed Src/FAK and ERK signalings activate GSK3-β, thus inhibiting nuclear accumulation of β-catenin. As a result, transcriptional expressions of two major gelatinases (MMP-2 and MMP-9) were significantly down-regulated. Consequently, migration and invasion of A549 human non-small-cell lung cancer cells were attenuated. Anti-metastatic effect of maclurin on A549 human non-small-cell lung cancer cells were diminished by the treatment of hydrogen peroxide, thus further implicating that the effect of maclurin may be strongly related with its anti-oxidative activity. Thus, our data indicate that the anti-metastatic effect of maclurin is exerted by anti-oxidative activity and inhibition of Src/FAK–ERK–β-catenin signaling pathway.

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

Abbreviations

NSCLC:

Non-small-cell lung cancer

MMP:

Matrix metalloproteinase

MAPK:

Mitogen-activated protein kinase

ROS:

Reactive oxygen species

References

  1. Basset P, Okada A, Chenard MP, Kannanb R, Stoll I, Anglard P, Bellocq JP, Rio MC (1997) Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol 15:535–541

    Article  CAS  PubMed  Google Scholar 

  2. Johnsen M, Lund LR, Rømer J, Almholt K, Danø K (1998) Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol 10:667–671

    Article  CAS  PubMed  Google Scholar 

  3. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737–749

    Article  CAS  PubMed  Google Scholar 

  4. Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr. (1993) Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7:1434–1441

    CAS  PubMed  Google Scholar 

  5. Bierbaum S, Hintze V, Scharnweber D (2012) Functionalization of biomaterial surfaces using artificial extracellular matrices. Biomatter 2:132–141

    Article  PubMed Central  PubMed  Google Scholar 

  6. Yodkeeree S, Ampasavate C, Sung B, Aggarwal BB, Limtrakul P (2010) Demethoxycurcumin suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur J Pharmacol 627:8–15

    Article  CAS  PubMed  Google Scholar 

  7. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25:9–34

    Article  CAS  PubMed  Google Scholar 

  8. Nyberg P, Salo T, Kalluri R (2008) Tumor microenvironment and angiogenesis. Front Biosci 13:6537–6553

    Article  CAS  PubMed  Google Scholar 

  9. Bae IH, Park MJ, Yoon SH, Kang SW, Lee SS, Choi KM, Um HD (2006) Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1. Cancer Res 66:4991–4995

    Article  CAS  PubMed  Google Scholar 

  10. Westermarck J, Kähäri VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792

    CAS  PubMed  Google Scholar 

  11. Hamaguchi M, Yamagata S, Thant AA, Xiao H, Iwata H, Mazaki T, Hanafusa H (1995) Augmentation of metalloproteinase (gelatinase) activity secreted from Rous sarcoma virus-infected cells correlates with transforming activity of src. Oncogene 10:1037–1043

    CAS  PubMed  Google Scholar 

  12. 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 

  13. Nishikawa M (2008) Reactive oxygen species in tumor metastasis. Cancer Lett 266:53–59

    Article  CAS  PubMed  Google Scholar 

  14. Nelson KK, Melendez JA (2004) Mitochondrial redox control of matrix metalloproteinases. Free Radic Biol Med 37:768–784

    Article  CAS  PubMed  Google Scholar 

  15. Giannoni E, Buricchi F, Raugei G, Ramponi G, Chiarugi P (2005) Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol 25:6391–6403

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Chang LW, Juang LJ, Wang BS, Wang MY, Tai HM, Hung WJ, Chen YJ, Huang MH (2011) Antioxidant and antityrosinase activity of mulberry (Morus alba L.) twigs and root bark. Food Chem Toxicol 49:785–790

    Article  CAS  PubMed  Google Scholar 

  17. Li X, Gao Y, Li F, Liang A, Xu Z, Bai Y, Mai W, Han L, Chen D (2014) Maclurin protects against hydroxyl radical-induced damages to mesenchymal stem cells: antioxidant evaluation and mechanistic insight. Chem Biol Interact 219C:221–228

    Article  Google Scholar 

  18. Kofujita H, Yaguchi M, Doi N, Suzuki K (2004) A novel cytotoxic prenylated flavonoid from the root of Morus alba. J Insect Biotechnol Sericology 73:113–116

    CAS  Google Scholar 

  19. Chen PN, Chu SC, Chiou HL, Kuo WH, Chiang CL, Hsieh YS (2006) Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line. Cancer Lett 235:248–259

    Article  CAS  PubMed  Google Scholar 

  20. Dulak J (2005) Nutraceuticals as anti-angiogenic agents: hopes and reality. J Physiol Pharmacol 56:51–67

    PubMed  Google Scholar 

  21. Yadav M, Jain S, Bhardwaj A, Nagpal R, Puniya M, Tomar R, Singh V, Parkash O, Prasad GB, Marotta F, Yadav H (2009) Biological and medicinal properties of grapes and their bioactive constituents: an update. J Med Food 12:473–484

    Article  CAS  PubMed  Google Scholar 

  22. Meeran SM, Katiyar SK (2008) Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci 13:2191–2202

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481:243–268

    Article  PubMed  Google Scholar 

  24. Oi N, Jeong CH, Nadas J, Cho YY, Pugliese A, Bode AM, Dong Z (2010) Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene A4hydrolase. Cancer Res 70:9755–9764

    Article  CAS  PubMed  Google Scholar 

  25. Kim MH, Son YJ, Lee SY, Yang WS, Yi YS, Yoon DH, Yang Y, Kim SH, Lee D, Rhee MH, Kang H, Kim TW, Sung GH, Cho JY (2013) JAK2-targeted anti-inflammatory effect of a resveratrol derivative 2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide. Biochem Pharmacol 86:1747–1761

    Article  CAS  PubMed  Google Scholar 

  26. Yeh CH, Yang JJ, Yang ML, Li YC, Kuan YH (2014) Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK–NF-κB pathway. Free Radic Biol Med 69:249–257

    Article  CAS  PubMed  Google Scholar 

  27. Giannoni E, Taddei ML, Chiarugi P (2010) Src redox regulation: again in the front line. Free Radic Biol Med 49:516–527

    Article  CAS  PubMed  Google Scholar 

  28. Son YO, Pratheeshkumar P, Wang L, Wang X, Fan J, Kim DH, Lee JY, Zhang Z, Lee JC, Shi X (2013) Reactive oxygen species mediate Cr(VI)-induced carcinogenesis through PI3 K/AKT-dependent activation of GSK-3b/b-catenin signaling. Toxicol Appl Pharmacol 271(2):239–248

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, Hung MC (2005) Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19:159–170

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology of Korea (2010-0023292) and the Gachon University research fund of 2014 (GCU-2014-0197).

Author information

Author notes

    Authors and Affiliations

    1. Department of Life Science, Gachon University, San 65, Bokjeong-Dong, Sujeong-Gu, Seongnam-Si, Gyeonggi-Do, 461-701, Korea

      Min Jung Ku, Ji Hyun Kim & Sang Yeol Lee

    2. Department of Dermatological Health Management, College of Health Science, Eulji University, Seongnam-Si, Gyeonggi-Do, 561-713, Korea

      Jongsung Lee

    3. Department of Genetic Engineering, Sungkyunkwan University, Suwon-Si, Gyeonggi-Do, 440-746, Korea

      Jae Youl Cho

    4. Division of Biotechnology, Korea University, Seoul, 136-701, Korea

      Taehoon Chun

    Authors
    1. Min Jung Ku
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ji Hyun Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jongsung Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Jae Youl Cho
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Taehoon Chun
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Sang Yeol Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Sang Yeol Lee.

    Additional information

    Min Jung Ku, Ji Hyun Kim, and Jongsung Lee have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Ku, M.J., Kim, J.H., Lee, J. et al. Maclurin suppresses migration and invasion of human non-small-cell lung cancer cells via anti-oxidative activity and inhibition of the Src/FAK–ERK–β-catenin pathway. Mol Cell Biochem 402, 243–252 (2015). https://doi.org/10.1007/s11010-015-2331-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11010-015-2331-4

    Keywords

    Search

    Navigation