Skip to main content
SpringerLink
Log in

Iron depletion strategy for targeted cancer therapy: utilizing the dual roles of neutrophil gelatinase-associated lipocalin protein

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Decreasing iron uptake and increasing iron efflux may result in cell death by oxidative inactivation of vital enzymes. Applying the dual function of neutrophil gelatinase-associated lipocalin (NGAL) could achieve the goal of iron depletion in the cancer cells. Tyr106, Lys125 or Lys134 was the key binding site for NGAL protein to sequester iron-chelating siderophores. In this study, we employed all bioactive peptides in peptide databank to dock with the siderophore-binding sites of NGAL protein by virtual screening. In addition, we performed molecular dynamics (MD) simulation to observe the molecular character and structural variation of ligand-protein interaction. Glu-Glu-Lys-Glu (EEKE), Glu-Glu-Asp-Cys-Lys (EEDCK), and Gly-Glu-Glu-Cys-Asp (GEECD) were selected preliminarily by rigorous scoring functions for further investigation. GEECD was excluded due to higher binding total energy than the others. Moreover, we also excluded EEKE due to larger influence to the stability of binding residues by the information of root mean square fluctuation (RMSF) and principal component analysis (PCA). Thus, we suggested that EEDCK was the potential bioactive peptide which had been proved to inhibit malignant cells for targeted cancer therapy.

Perspective drug design of occupying the siderophore-binding sites of NGAL outside the cell temporarily by a potential short peptide until NGAL enters into the cell, and releasing the siderophore-binding sites inside the cell.

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

Scheme 1
Scheme 2
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  1. Schumacker PT (2015) Reactive oxygen species in cancer: a dance with the devil. Cancer Cell 27:156–157

    Article  CAS  Google Scholar 

  2. Bystrom LM, Guzman ML, Rivella S (2014) Iron and reactive oxygen species: friends or foes of cancer cells? Antioxid Redox Signal 20:1917–1924

    Article  CAS  Google Scholar 

  3. Torti SV, Torti FM (2013) Iron and cancer: more ore to be mined. Nat Rev Cancer 13:342–355

    Article  CAS  Google Scholar 

  4. Dixon SJ, Stockwell BR (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10:9–17

    Article  CAS  Google Scholar 

  5. Andrews NC (2008) Forging a field: the golden age of iron biology. Blood 112:219–230

    Article  CAS  Google Scholar 

  6. Nagai K, Nakahata S, Shimosaki S, Tamura T, Kondo Y, Baba T, Taki T, Taniwaki M, Kurosawa G, Sudo Y, Okada S, Sakoda S, Morishita K (2014) Development of a complete human anti-human transferrin receptor C antibody as a novel marker of oral dysplasia and oral cancer. Cancer Med 3:1085–1099

    Article  CAS  Google Scholar 

  7. Daniels TR, Bernabeu E, Rodriguez JA, Patel S, Kozman M, Chiappetta DA, Holler E, Ljubimova JY, Helguera G, Penichet ML (2012) The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta 1820:291–317

    Article  CAS  Google Scholar 

  8. Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10:1045–1056

    Article  CAS  Google Scholar 

  9. Devireddy LR, Gazin C, Zhu X, Green MR (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123:1293–1305

    Article  CAS  Google Scholar 

  10. Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J (2007) Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 18:407–413

    Article  CAS  Google Scholar 

  11. Bolignano D, Donato V, Lacquaniti A, Fazio MR, Bono C, Coppolino G, Buemi M (2010) Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Lett 288:10–16

    Article  CAS  Google Scholar 

  12. Correnti C, Richardson V, Sia AK, Bandaranayake AD, Ruiz M, Suryo Rahmanto Y, Kovacevic Z, Clifton MC, Holmes MA, Kaiser BK, Barasch J, Raymond KN, Richardson DR, Strong RK (2012) Siderocalin/Lcn2/NGAL/24p3 does not drive apoptosis through gentisic acid mediated iron withdrawal in hematopoietic cell lines. PLoS One 7, e43696

    Article  CAS  Google Scholar 

  13. Gomez-Casado C, Roth-Walter F, Jensen-Jarolim E, Diaz-Perales A, Pacios LF (2013) Modeling iron-catecholates binding to NGAL protein. J Mol Graph Model 45:111–121

    Article  CAS  Google Scholar 

  14. Tang HC, Chen YC (2015) Insight into molecular dynamics simulation of BRAF(V600E) and potent novel inhibitors for malignant melanoma. Int J Nanomedicine 10:3131–3146

    Article  CAS  Google Scholar 

  15. Mueller S, Coleman JR, Papamichail D, Ward CB, Nimnual A, Futcher B, Skiena S, Wimmer E (2010) Live attenuated influenza virus vaccines by computer-aided rational design. Nat Biotechnol 28:723–726

    Article  CAS  Google Scholar 

  16. Mandell DJ, Kortemme T (2009) Computer-aided design of functional protein interactions. Nat Chem Biol 5:797–807

    Article  CAS  Google Scholar 

  17. Tang HC, Chen YC (2015) Identification of tyrosinase inhibitors from traditional Chinese medicines for the management of hyperpigmentation. Springerplus 4:184

    Article  Google Scholar 

  18. Chen CY (2013) A novel integrated framework and improved methodology of computer-aided drug design. Curr Top Med Chem 13:965–988

    Article  CAS  Google Scholar 

  19. Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, Mackerell AD Jr (2010) CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671–690

    CAS  Google Scholar 

  20. Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845–854

    Article  CAS  Google Scholar 

  21. Parks SK, Chiche J, Pouyssegur J (2013) Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer 13:611–623

    Article  CAS  Google Scholar 

  22. Liu X, Madhankumar AB, Slagle-Webb B, Sheehan JM, Surguladze N, Connor JR (2011) Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents. Cancer Res 71:2240–2249

    Article  CAS  Google Scholar 

  23. Iannetti A, Pacifico F, Acquaviva R, Lavorgna A, Crescenzi E, Vascotto C, Tell G, Salzano AM, Scaloni A, Vuttariello E, Chiappetta G, Formisano S, Leonardi A (2008) The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci U S A 105:14058–14063

    Article  CAS  Google Scholar 

  24. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S (2014) Drug resistance in cancer: an overview. Cancers (Basel) 6:1769–1792

    Article  CAS  Google Scholar 

  25. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093

    Article  CAS  Google Scholar 

  26. Candido S, Maestro R, Polesel J, Catania A, Maira F, Signorelli SS, McCubrey JA, Libra M (2014) Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer. Oncotarget 5:1576–1594

    Article  Google Scholar 

  27. Paragas N, Qiu A, Zhang Q, Samstein B, Deng SX, Schmidt-Ott KM, Viltard M, Yu W, Forster CS, Gong G, Liu Y, Kulkarni R, Mori K, Kalandadze A, Ratner AJ, Devarajan P, Landry DW, D’Agati V, Lin CS, Barasch J (2011) The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat Med 17:216–222

    Article  CAS  Google Scholar 

  28. Duman H, Topal IO, Kocaturk E and Duman MA (2015) Evaluation of anxiety, depression, and quality of life in patients with acne vulgaris, and quality of life in their families. Dermatologica Sinica doi:10.1016/j.dsi.2015.07.002

  29. Liu WH, Liu TC, Mong MC (2015) Antibacterial effects and action modes of asiatic acid. Biomedicine (Taipei) 5:16

    Article  Google Scholar 

  30. Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM (2008) Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells. J Clin Invest 118:1468–1478

    Article  CAS  Google Scholar 

  31. Richardson DR (2005) 24p3 and its receptor: dawn of a new iron age? Cell 123:1175–1177

    Article  CAS  Google Scholar 

  32. Sun A, Fang J, Yan J (2013) Advance and development in research of bacterial drug-resistance signaling mechanism and multiple antigenic peptide-based vaccines. Zhejiang Da Xue Xue Bao Yi Xue Ban 42:125–130

    CAS  Google Scholar 

  33. Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21:297–308

    Article  CAS  Google Scholar 

  34. Prajapati SC, Chauhan SS (2011) Dipeptidyl peptidase III: a multifaceted oligopeptide N-end cutter. FEBS J 278:3256–3276

    Article  CAS  Google Scholar 

  35. Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard N (2005) The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 579:773–777

    Article  CAS  Google Scholar 

  36. Abergel RJ, Clifton MC, Pizarro JC, Warner JA, Shuh DK, Strong RK, Raymond KN (2008) The siderocalin/enterobactin interaction: a link between mammalian immunity and bacterial iron transport. J Am Chem Soc 130:11524–11534

    Article  CAS  Google Scholar 

  37. Bao G, Clifton M, Hoette TM, Mori K, Deng SX, Qiu A, Viltard M, Williams D, Paragas N, Leete T, Kulkarni R, Li X, Lee B, Kalandadze A, Ratner AJ, Pizarro JC, Schmidt-Ott KM, Landry DW, Raymond KN, Strong RK, Barasch J (2010) Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol 6:602–609

    Article  CAS  Google Scholar 

  38. Correnti C, Strong RK (2012) Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool. J Biol Chem 287:13524–13531

    Article  CAS  Google Scholar 

  39. Masse A, Ramirez LH, Bindoula G, Grillon C, Wdzieczak-Bakala J, Raddassi K, Deschamps de Paillette E, Mencia-Huerta JM, Koscielny S, Potier P, Sainteny F, Carde P (1998) The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (Goralatide) protects from doxorubicin-induced toxicity: improvement in mice survival and protection of bone marrow stem cells and progenitors. Blood 91:441–449

    CAS  Google Scholar 

  40. Terui Y, Tomizuka H, Mishima Y, Ikeda M, Kasahara T, Uwai M, Mori M, Itoh T, Tanaka M, Yamada M, Shimamura S, Ishizaka Y, Ozawa K, Hatake K (1999) NH2-terminal pentapeptide of endothelial interleukin 8 is responsible for the induction of apoptosis in leukemic cells and has an antitumor effect in vivo. Cancer Res 59:5651–5655

    CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from Asia University (Asia102-CMU-1, Asia102-CMU-2, and Asia102-CMU-3), China Medical University Hospital (DMR-104-084, DMR-104-118, and DMR-102-001) and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. This study was supported partly by the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-113019).

Author information

Authors and Affiliations

  1. Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan

    Hsin-Chieh Tang, Pei-Chun Chang & Yu-Chian Chen

  2. Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, 40402, Taiwan

    Yu-Chian Chen

  3. Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, 40402, Taiwan

    Yu-Chian Chen

Authors
  1. Hsin-Chieh Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pei-Chun Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Chian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Chian Chen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, HC., Chang, PC. & Chen, YC. Iron depletion strategy for targeted cancer therapy: utilizing the dual roles of neutrophil gelatinase-associated lipocalin protein. J Mol Model 22, 32 (2016). https://doi.org/10.1007/s00894-015-2897-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-015-2897-5

Keywords

Search

Navigation