Association Between Nuclear Receptor Coactivator 1 and Stem Cell Signaling Pathway and Identification of Natural NCOA1 Inhibitors: An in-silico Study

  • Pushpendra Singh
  • Prem P. Kushwaha
  • Atul K. Singh
  • Shashank Kumar


Nuclear receptor coactivator 1 (NCOA1) is overexpressed in various cancer and is associated with disease resistance and its poor prognosis. miRNAs are the short stretch of noncoding nucleotide sequence responsible for RNA silencing and post-transcriptional gene regulation. Deregulated expression of miRNAs is associated with carcinogenesis. Present study focuses on the evolution of the NCOA1, identification of miRNAs (and their associated pathways) occupied in the regulation of NCOA1, and natural inhibitors of the protein by using various online and offline computational tools such as, molecular evolutionary genetics analysis (MEGA6) tool, DIANA-mirPathv3 software and Maestro 9.6 (Schrödinger Inc) respectively. The phylogenetic analyses of different isolates of nuclear receptor coactivator show that humans formed a separate clade. Five miRNAs (has-mir-186-3p, has-mir-27a-3p, has-mir-27b-3p, has-mir-7-2-3p, and has-mir-374a-5p) occupied in the regulation of NCOA1 protein were found to highly associated with cancer stem cell pathway. Excellent Dock Score of kaempferol and hesperidin analogs was found against NCOA1 active site. The interactions pattern underlined the involvement of lipophilic, electrostatic, hydrogen bonding, π-cation stacking, and π-π stacking mode of interaction at the active site. Thus analog of kaempferol and hesperidin may contribute to developing as a potential agent for cancer chemotherapy and resistance. Association of recognized miRNAs with NCOA1 protein strengthens its role in cancer resistance through stem cell signaling pathways.


Nuclear receptor coactivator 1 Cancer Phylogenetic tree Natural compounds Maestro 9.6 Pathway prediction 



PS and PPK acknowledge Indian Council of Medical Research (ICMR), India and UGC-CSIR, India respectively for providing the financial assistance in the form of Postdoc and Junior Research Fellowship. SK acknowledges the Central University of Punjab for providing infrastructure facilities.


  1. Anzick SL, Kononen J, Walker RL, Azorsa D, Tanner MM, Guan X, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997;277(5328):965–8.PubMedCrossRefGoogle Scholar
  2. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;1:289–300.Google Scholar
  3. Bhanot A, Sharma R, Noolvi MN. Natural sources as potential anti-cancer agents: A review. Int J Phytomed. 2011;3(1):09–26.Google Scholar
  4. Calderón-Montaño JM, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem. 2011;11(4):298–344.PubMedCrossRefGoogle Scholar
  5. Carotenuto F, Albertini MC, Coletti D, Vilmercati A, Campanella L, Darzynkiewicz Z, Teodori L. How diet intervention via modulation of DNA damage response through microRNAs may have an effect on cancer prevention and aging, an in silico study. Int J Mol Sci. 2016;17(5):1–21.CrossRefGoogle Scholar
  6. Chen X, Liu Z, Xu J. The cooperative function of nuclear receptor coactivator 1 (NCOA1) and NCOA3 in placental development and embryo survival. Mol Endocrinol. 2010;24(10):1917–34.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cherigo L, Lopez D, Martinez-Luis S. Marine natural products as breast cancer resistance protein inhibitors. Mar Drugs. 2015;13(4):2010–29.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Cragg GM, Newman DJ. Plants as a source of anti-cancer agents. J Ethnopharmacol. 2005;100(1–2):72–9.PubMedCrossRefGoogle Scholar
  9. DaRocha AB, Lopes RM, Schwartsmann G. Natural products in anticancer therapy. Curr Opin Pharmacol. 2001;1(4):364–9.CrossRefGoogle Scholar
  10. Febriansah R, Putri DDP, Sarmoko, Nurulita NA, Meiyanto E, Nugroho AE. Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin. Asian Pac J Trop Biomed. 2014;4(3):228–33.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Felsenstein J. Confidence limits on phylogenies: an approach using the bootstrap. Evolution. 1985;39(4):783–91.CrossRefGoogle Scholar
  12. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739–49.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006;49(21):6177–96.PubMedCrossRefGoogle Scholar
  14. Ganatra S H. Inhibition studies of naturally occurring terpene based compounds with cyclin-dependent kinase 2 enzyme. J Comput Sci Syst Biol. 2012;5(3):68–73.CrossRefGoogle Scholar
  15. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47(7):1750–9.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Hillman GG. Dietary agents in cancer chemoprevention and treatment. J Oncol. 2012;21:209–19.Google Scholar
  17. Huang W, He T, Chai C, Yang Y, Zheng Y, Zhou P, Qiao X, Zhang B, Liu Z, Wang J, Shi C. Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression. PLoS One. 2012;7(5):1–17.Google Scholar
  18. Jae YC, Park J. Contribution of natural inhibitors to the understanding of the PI3K/PDK1/PKB pathway in the insulin-mediated intracellular signaling cascade. Int J Mol Sci. 2008;9(11):2217–30.CrossRefGoogle Scholar
  19. Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Deliv Rev. 2002;54(3):355–66.PubMedCrossRefGoogle Scholar
  20. Jorgensen WL, Tirado-Rives J. The OPLS potential functions for proteins. Energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc. 1988;110(6):1657–66.PubMedCrossRefGoogle Scholar
  21. Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc. 1996;118(45):11225–36.CrossRefGoogle Scholar
  22. Kamaraj S, Ramakrishnan G, Anandakumar P, Jagan S, Devaki T. Antioxidant and anticancer efficacy of hesperidin in benzo(a)pyrene induced lung carcinogenesis in mice. Investig New Drugs. 2009;27(3):214–22.CrossRefGoogle Scholar
  23. Kim SK. Marine carbohydrates: fundamentals and applications. Oxford: Elsevier; 2014.Google Scholar
  24. Kishimoto H, Wang Z, Bhat-Nakshatri P, Chang D, Clarke R, Nakshatri H. The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1α/CXCL12. Carcinogenesis. 2005;26(10):1706–15.PubMedCrossRefGoogle Scholar
  25. Kumar S, Chashoo G, Saxena AK, Pandey AK. Parthenium hysterophorus: a probable source of anticancer, antioxidant and anti-HIV agents. Biomed Res Int. 2013;2013:1–11.Google Scholar
  26. Lauria A, Ippolito M, Almerico AM. Inside the Hsp90 inhibitors binding mode through induced fit docking. J Mol Graph Model. 2009;27(6):712–22.PubMedCrossRefGoogle Scholar
  27. Lee CJ, Wilson L, Jordan MA, Nguyen V, Tang J, Smiyun G. Hesperidin suppressed proliferations of both human breast cancer and androgen-dependent prostate cancer cells. Phytother Res. 2010;24(S1):S15–9.PubMedCrossRefGoogle Scholar
  28. Lee J-C, Hou M-F, Huang H-W, Chang F-R, Yeh C-C, Tang J-Y, Chang HW. Marine algal natural products with anti-oxidative, anti-inflammatory, and anti-cancer properties. Cancer Cell Int. 2013;13(1):1–7.CrossRefGoogle Scholar
  29. Liao L, Chen X, Wang S, Parlow AF, Xu J. Steroid receptor coactivator 3 maintains circulating insulin-like growth factor I (IGF-I) by controlling IGF-binding protein 3 expression. Mol Cell Biol. 2008;28(7):2460–9.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Lu JJ, Crimin K, Goodwin JT, Crivori P, Orrenius C, Xing L, Tandler PJ, Vidmar TJ, Amore BM, Wilson AG, Stouten PF. Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat. J Med Chem. 2004;47(24):6104–7.PubMedCrossRefGoogle Scholar
  31. Luo H, Rankin GO, Liu L, Daddysman MK, Jiang BH, Chen YC. Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutr Cancer. 2009;61(4):554–63.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Mayer AMS, Gustafson KR. Marine pharmacology in 2001-2: anti-tumour and cytotoxic compounds. Eur J Cancer. 2004;40(18):2676–704.PubMedCrossRefGoogle Scholar
  33. Mayer AMS, Gustafson KR. Marine pharmacology in 2003–2004: anti-tumour and cytotoxic compounds. Eur J Cancer. 2006;42(14):2241–70.PubMedCrossRefGoogle Scholar
  34. Mayer AMS, Gustafson KR. Marine pharmacology in 2005–2006: antitumour and cytotoxic compounds. Eur J Cancer. 2009;44(16):2357–87.CrossRefGoogle Scholar
  35. Moussavou G, Kwak DH, Obiang-Obonou BW, Maranguy CAO, Dinzouna-Boutamba SD, Lee DH, Pissibanganga OG, Ko K, Seo JI, Choo YK. Anticancer effects of different seaweeds on human colon and breast cancers. Mar Drugs. 2014;12(9):4898–911.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Muthuirulappan S, Francis SP. Anti-cancer mechanism and possibility of nano-suspension formulation for a marine algae product fucoxanthin. Asian Pac J Cancer Prev. 2013;14(4):2213–6.PubMedCrossRefGoogle Scholar
  37. Oh A. The nuclear receptor coactivator AIB1 mediates insulin-like growth factor I-induced phenotypic changes in human breast cancer cells. Cancer Res. 2014;64:8299–308.CrossRefGoogle Scholar
  38. Phosrithong N, Ungwitayatorn J. Molecular docking study on anticancer activity of plant-derived natural products. Med Chem Res. 2010;19(8):817–35.CrossRefGoogle Scholar
  39. Qin L, Wu Y, Toneff MJ, Li D, Liao L, Gao X, Bane FT, Tien JC, Xu Y, Feng Z, Yang Z. NCOA1 directly targets M-CSF1 expression to promote breast cancer metastasis. Cancer Res. 2015a;74(13):3477–88.CrossRefGoogle Scholar
  40. Qin L, Xu Y, Xu Y, Ma G, Liao L, Wu Y, Li Y, Wang X, Wang X, Jiang J, Wang J. NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1alpha- and AP-1-mediated VEGFa transcription. Oncotarget. 2015b;6(27):23890–904.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Razeto A, Ramakrishnan V, Litterst CM, Giller K, Griesinger C, Carlomagno T, Lakomek N, Heimburg T, Lodrini M, Pfitzner E, Becker S. Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. J Mol Biol. 2004;336(2):319–29.PubMedCrossRefGoogle Scholar
  42. Roell D, Baniahmad A. The natural compounds atraric acid and N-butylbenzene-sulfonamide as antagonists of the human androgen receptor and inhibitors of prostate cancer cell growth. Mol Cell Endocrinol. 2011;332(1–2):1–8.PubMedCrossRefGoogle Scholar
  43. Sarkar FH, Li Y. Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res. 2006;66(7):3347–50.PubMedCrossRefGoogle Scholar
  44. Sawadogo W, Schumacher M, Teiten MH, Cerella C, Dicato M, Diederich M. A survey of marine natural compounds and their derivatives with anti-cancer activity reported in 2011. Molecules. 2013;18(4):3641–73.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Sawadogo WR, Boly R, Cerella C, Teiten MH, Dicato M, Diederich M. A survey of marine natural compounds and their derivatives with anti-cancer activity reported in 2012. Molecules. 2015;20(4):7097–142.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput. 2010;6(5):1509–19.PubMedCrossRefGoogle Scholar
  47. Singh P, Bast F. In silico molecular docking study of natural compounds on wild and mutated epidermal growth factor receptor. Med Chem Res. 2014a;23(12):5074–85.CrossRefGoogle Scholar
  48. Singh P, Bast F. Multitargeted molecular docking study of plant-derived natural products on phosphoinositide-3 kinase pathway components. Med Chem Res. 2014b;23(4):1690–700.CrossRefGoogle Scholar
  49. Singh P, Bast F. High-throughput virtual screening, identification and in vitro biological evaluation of novel inhibitors of signal transducer and activator of transcription 3. Med Chem Res. 2015a;24(6):2694–708.CrossRefGoogle Scholar
  50. Singh P, Bast F. Screening and biological evaluation of myricetin as a multiple target inhibitor insulin, epidermal growth factor, and androgen receptor; In silico and in vitro. Investig New Drugs. 2015b;33(3):575–93.CrossRefGoogle Scholar
  51. Singh P, Bast F. Screening of multi-targeted natural compounds for receptor tyrosine kinases inhibitors and biological evaluation on cancer cell lines, in silico and in vitro. Med Oncol. 2015c;32(9):1–18.Google Scholar
  52. Singh P, Alex JM, Bast F. Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol. 2014;31(1):1–14.CrossRefGoogle Scholar
  53. Tien JC, Liu Z, Liao L, Wang F, Xu Y, Wu YL, Zhou N, Ittmann MM, Xu J. The steroid receptor coactivator-3 is required for the development of castration-resistant prostate cancer. Cancer Res. 2013;73(13):3997–4008.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Tien JCY, Liao L, Liu Y, Liu Z, Lee DK, Wang F, Xu J. The steroid receptor coactivator-3 is required for developing neuroendocrine tumor in the mouse prostate. Int J Biol Sci. 2014;10(10):1116–27.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Vallianatou T, Lambrinidis G, Tsantili-Kakoulidou A. In silico prediction of human serum albumin binding for drug leads. Expert Opin Drug Discov. 2013;8(5):583–95.PubMedCrossRefGoogle Scholar
  56. Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, Dalamagas T, Hatzigeorgiou AG. DIANA-miRPath v3. 0: deciphering microRNA function with experimental support. Nucleic Acids Res. 2015;43(W1):W460–6.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Wang H, Gao M, Wang J. Kaempferol inhibits cancer cell growth by antagonizing estrogen-related receptor α and ϒ activities. Cell Biol Int. 2013;37(11):1190–6.PubMedGoogle Scholar
  58. Xu J, Li Q. Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol Endocrinol. 2003;17:1681–92.PubMedCrossRefGoogle Scholar
  59. Xu J, Wu R-C, O’Malley BW. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer. 2009;9(9):615–30.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Pushpendra Singh
    • 1
  • Prem P. Kushwaha
    • 2
  • Atul K. Singh
    • 2
  • Shashank Kumar
    • 2
  1. 1.Tumor Biology LaboratoryNational Institute of PathologyNew DelhiIndia
  2. 2.Department of Biochemistry and Microbial SciencesCentral University of PunjabBathindaIndia

Personalised recommendations