Tumor Biology

, Volume 37, Issue 7, pp 9375–9385 | Cite as

Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells

  • Emelia A. Assar
  • Magdalena Castellano Vidalle
  • Mridula Chopra
  • Sassan Hafizi
Original Article


We studied the effect of the potent dietary antioxidant lycopene on multiple points along the nuclear factor kappa B (NF-κB) signaling pathway in prostate and breast cancer cells. Lycopene significantly inhibited prostate and breast cancer cell growth at physiologically relevant concentrations of ≥1.25 μM. Similar concentrations also caused a 30–40 % reduction in inhibitor of kappa B (IκB) phosphorylation in the cells, as determined by western blotting. Furthermore, the same degree of inhibition by lycopene was observed for NF-κB transcriptional activity, as determined by reporter gene assay. Concomitant with this, immunofluorescence staining of lycopene-treated cells showed a significant suppression (≥25 %) of TNF-induced NF-κB p65 subunit nuclear translocation. Further probing of lycopene’s effects on upstream elements of the NF-κB pathway showed a 25 % inhibition of both activity of recombinant IκB kinase β (IKKβ) kinase in a cell-free in vitro assay, as well as activity of IKKβ immunoprecipitated from MDA-MB-231 cells treated with lycopene. In conclusion, the anticancer properties of lycopene may occur through inhibition of the NF-κB signaling pathway, beginning at the early stage of cytoplasmic IKK kinase activity, which then leads to reduced NF-κB-responsive gene regulation. Furthermore, these effects in cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo.


Prostate cancer Breast cancer IκB kinase Lycopene NF-κB Nutrition 



Nuclear factor kappa B


Inhibitor of kappa B


IκB kinase



This study was funded by the Institute of Biomedical and Biomolecular Science (IBBS), University of Portsmouth. The authors thank DSM Nutritional Products for their generous gift of the lycopene used in the present study. The authors are also grateful to Mr. Salman Goudarzi, Miss Mikaella Vouri, and Mr. Phil Warren, School of Pharmacy and Biomedical Sciences, University of Portsmouth, for technical assistance.

Author contributions

EA and MCV performed the experiments, analyzed the results, and wrote the paper. MC and SH conceived of the study, designed the experiments, analyzed the results and wrote the paper.

Compliance with ethical standards

Conflicts of interest


Supplementary material

13277_2016_4798_MOESM1_ESM.docx (1 mb)
Fig. S1 (DOCX 1065 kb)


  1. 1.
    Cancer incidence statistics. Cancer Research UK.
  2. 2.
    Chan JM, Gann PH, Giovannucci EL. Role of diet in prostate cancer development and progression. J Clin Oncol. 2005;23(32):8152–60.CrossRefPubMedGoogle Scholar
  3. 3.
    Giovannucci E, Ascherio A, Rimm EB, et al. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst. 1995;87(23):1767–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Barber NJ, Barber J. Lycopene and prostate cancer. Prostate Cancer Prostatic Dis. 2002;5(1):6–12.CrossRefPubMedGoogle Scholar
  5. 5.
    Gann PH, Ma J, Giovannucci E, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res. 1999;59(6):1225–30.PubMedGoogle Scholar
  6. 6.
    Sesso HD, Buring JE, Zhang SM, et al. Dietary and plasma lycopene and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(5):1074–81.CrossRefPubMedGoogle Scholar
  7. 7.
    Jarvinen R, Knekt P, Seppanen R, et al. Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett. 1997;114(1-2):251–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Levy J, Bosin E, Feldman B, et al. Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer. 1995;24(3):257–66.CrossRefPubMedGoogle Scholar
  9. 9.
    Talvas J, Caris-Veyrat C, Guy L, et al. Differential effects of lycopene consumed in tomato paste and lycopene in the form of a purified extract on target genes of cancer prostatic cells. Am J Clin Nutr. 2010;91(6):1716–24.CrossRefPubMedGoogle Scholar
  10. 10.
    Prakash P, Russell RM, Krinsky NI. In vitro inhibition of proliferation of estrogen-dependent and estrogen-independent human breast cancer cells treated with carotenoids or retinoids. J Nutr. 2001;131(5):1574–80.PubMedGoogle Scholar
  11. 11.
    Fornelli F, Leone A, Verdesca I, et al. The influence of lycopene on the proliferation of human breast cell line (MCF-7). Toxicol In Vitro. 2007;21(2):217–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Gloria NF, Soares N, Brand C, et al. Lycopene and beta-carotene induce cell-cycle arrest and apoptosis in human breast cancer cell lines. Anticancer Res. 2014;34(3):1377–86.PubMedGoogle Scholar
  13. 13.
    Palozza P, Catalano A, Simone R, et al. Lycopene as a guardian of redox signalling. Acta Biochim Pol. 2012;59(1):21–5.PubMedGoogle Scholar
  14. 14.
    Siler U, Barella L, Spitzer V, et al. Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. FASEB J. 2004;18(9):1019–21.PubMedGoogle Scholar
  15. 15.
    Herzog A, Siler U, Spitzer V, et al. Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J. 2005;19(2):272–4.PubMedGoogle Scholar
  16. 16.
    Kim L, Rao AV, Rao LG. Effect of lycopene on prostate LNCaP cancer cells in culture. J Med Food. 2002;5(4):181–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Kotake-Nara E, Kushiro M, Zhang H, et al. Carotenoids affect proliferation of human prostate cancer cells. J Nutr. 2001;131(12):3303–6.PubMedGoogle Scholar
  18. 18.
    Hantz HL, Young LF, Martin KR. Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med (Maywood). 2005;230(3):171–9.Google Scholar
  19. 19.
    Hall AK. Liarozole amplifies retinoid-induced apoptosis in human prostate cancer cells. Anti-cancer Drugs. 1996;7(3):312–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Elgass S, Cooper A, Chopra M. Lycopene inhibits angiogenesis in human umbilical vein endothelial cells and rat aortic rings. Br J Nutr. 2012;108(3):431–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Elgass S, Cooper A, Chopra M. Lycopene treatment of prostate cancer cell lines inhibits adhesion and migration properties of the cells. Int J Med Sci. 2014;11(9):948–54.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Orlowski RZ, Baldwin Jr AS. NF-kappaB as a therapeutic target in cancer. Trends Mol Med. 2002;8(8):385–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Gasparian AV, Yao YJ, Kowalczyk D, et al. The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. J Cell Sci. 2002;115(Pt 1):141–51.PubMedGoogle Scholar
  24. 24.
    Sweeney C, Li L, Shanmugam R, et al. Nuclear factor-kappaB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate. Clin Cancer Res. 2004;10(16):5501–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Lessard L, Begin LR, Gleave ME, et al. Nuclear localisation of nuclear factor-kappaB transcription factors in prostate cancer: an immunohistochemical study. Br J Cancer. 2005;93(9):1019–23.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Huang S, Pettaway CA, Uehara H, et al. Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20(31):4188–97.CrossRefPubMedGoogle Scholar
  27. 27.
    Nakshatri H, Bhat-Nakshatri P, Martin DA, et al. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997;17(7):3629–39.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature. 2001;411(6841):1017–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Takeshima M, Ono M, Higuchi T, et al. Anti-proliferative and apoptosis-inducing activity of lycopene against three subtypes of human breast cancer cell lines. Cancer Sci. 2014;105(3):252–7.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cogswell PC, Guttridge DC, Funkhouser WK, et al. Selective activation of NF-kappa B subunits in human breast cancer: potential roles for NF-kappa B2/p52 and for Bcl-3. Oncogene. 2000;19(9):1123–31.CrossRefPubMedGoogle Scholar
  31. 31.
    Jiao X, Wood LD, Lindman M, et al. Somatic mutations in the Notch, NF-KB, PIK3CA, and Hedgehog pathways in human breast cancers. Genes Chromosomes Cancer. 2012;51(5):480–9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18(49):6938–47.CrossRefPubMedGoogle Scholar
  33. 33.
    Chuffa LG, Fioruci-Fontanelli BA, Mendes LO, et al. Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer. BMC Cancer. 2015;15:34.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Dinicola S, Pasqualato A, Cucina A, et al. Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion. Eur J Nutr. 2014;53(2):421–31.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen J, Creed A, Chen AY, et al. Nobiletin suppresses cell viability through AKT pathways in PC-3 and DU-145 prostate cancer cells. BMC Pharmacol Toxicol. 2014;15:59.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Palozza P, Colangelo M, Simone R, et al. Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis. 2010;31(10):1813–21.CrossRefPubMedGoogle Scholar
  37. 37.
    Huang CS, Shih MK, Chuang CH, et al. Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. J Nutr. 2005;135(9):2119–23.PubMedGoogle Scholar
  38. 38.
    Lin CY, Huang CS, Hu ML. The use of fetal bovine serum as delivery vehicle to improve the uptake and stability of lycopene in cell culture studies. Br J Nutr. 2007;98(1):226–32.CrossRefPubMedGoogle Scholar
  39. 39.
    An Q, Fillmore HL, Vouri M, et al. Brain tumor cell line authentication, an efficient alternative to capillary electrophoresis by using a microfluidics-based system. Neuro Oncology. 2014;16(2):265–73.CrossRefPubMedGoogle Scholar
  40. 40.
    Wang L, Ning S. Interferon regulatory factor 4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. J Virol. 2013;87(17):9672–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Shachaf CM, Perez OD, Youssef S, et al. Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis. Blood. 2007;110(7):2674–84.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Thiery G, Shchepinov MS, Southern EM, et al. Multiplex target protein imaging in tissue sections by mass spectrometry—TAMSIM. Rapid Commun Mass Spectrom. 2007;21(6):823–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Camperio C, Muscolini M, Volpe E, et al. CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes. Immunol Lett. 2014;158(1-2):134–42.CrossRefPubMedGoogle Scholar
  44. 44.
    Hampson A, O’Connor A, Smolenski A. Synaptotagmin-like protein 4 and Rab8 interact and increase dense granule release in platelets. J Thromb Haemost. 2013;11(1):161–8.CrossRefPubMedGoogle Scholar
  45. 45.
    DiDonato JA, Hayakawa M, Rothwarf DM, et al. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997;388(6642):548–54.CrossRefPubMedGoogle Scholar
  46. 46.
    Amir H, Karas M, Giat J, et al. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer. 1999;33(1):105–12.CrossRefPubMedGoogle Scholar
  47. 47.
    Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev. 2001;10(8):861–8.PubMedGoogle Scholar
  48. 48.
    Hwang ES, Bowen PE. Cell cycle arrest and induction of apoptosis by lycopene in LNCaP human prostate cancer cells. J Med Food. 2004;7(3):284–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Tang L, Jin T, Zeng X, et al. Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr. 2005;135(2):287–90.PubMedGoogle Scholar
  50. 50.
    Karas M, Amir H, Fishman D, et al. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer. 2000;36(1):101–11.CrossRefPubMedGoogle Scholar
  51. 51.
    Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. 2003;92(4):375–8. discussion 8.CrossRefPubMedGoogle Scholar
  52. 52.
    van Breemen RB, Xu X, Viana MA, et al. Liquid chromatography-mass spectrometry of cis- and all-trans-lycopene in human serum and prostate tissue after dietary supplementation with tomato sauce. J Agric Food Chem. 2002;50(8):2214–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Kim GY, Kim JH, Ahn SC, et al. Lycopene suppresses the lipopolysaccharide-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and nuclear factor-kappaB. Immunology. 2004;113(2):203–11.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Viatour P, Merville MP, Bours V, et al. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci. 2005;30(1):43–52.CrossRefPubMedGoogle Scholar
  55. 55.
    Sfanos KS, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology. 2012;60(1):199–215.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7(4):256–69.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Mercurio F, Zhu H, Murray BW, et al. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science. 1997;278(5339):860–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109(Suppl):S81–96.CrossRefPubMedGoogle Scholar
  60. 60.
    Linnewiel-Hermoni K, Motro Y, Miller Y, et al. Carotenoid derivatives inhibit nuclear factor kappa B activity in bone and cancer cells by targeting key thiol groups. Free Radic Biol Med. 2014;75:105–20.CrossRefPubMedGoogle Scholar
  61. 61.
    Puri T, Goyal S, Julka PK, et al. Lycopene in treatment of high-grade gliomas: a pilot study. Neurol India. 2010;58(1):20–3.CrossRefPubMedGoogle Scholar
  62. 62.
    Kumar NB, Besterman-Dahan K, Kang L, et al. Results of a randomized clinical trial of the action of several doses of lycopene in localized prostate cancer: administration prior to radical prostatectomy. Clin Med Urol. 2008;1:1–14.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Olmedilla B, Granado F, Southon S, et al. A European multicentre, placebo-controlled supplementation study with alpha-tocopherol, carotene-rich palm oil, lutein or lycopene: analysis of serum responses. Clin Sci (Lond). 2002;102(4):447–56.CrossRefGoogle Scholar
  64. 64.
    Eddy SF, Guo S, Demicco EG, et al. Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res. 2005;65(24):11375–83.CrossRefPubMedGoogle Scholar
  65. 65.
    Romieu-Mourez R, Landesman-Bollag E, Seldin DC, et al. Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. Cancer Res. 2001;61(9):3810–8.PubMedGoogle Scholar
  66. 66.
    Tian H, Zhang B, Di J, et al. Keap1: one stone kills three birds Nrf2, IKKbeta and Bcl-2/Bcl-xL. Cancer Lett. 2012;325(1):26–34.CrossRefPubMedGoogle Scholar
  67. 67.
    Lian F, Wang XD. Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. Int J Cancer. 2008;123(6):1262–8.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Mann GE, Niehueser-Saran J, Watson A, et al. Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: implications for atherosclerosis and preeclampsia. Sheng Li Xue Bao. 2007;59(2):117–27.PubMedGoogle Scholar
  69. 69.
    Forman HJ, Davies KJ, Ursini F. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med. 2014;66:24–35.CrossRefPubMedGoogle Scholar
  70. 70.
    Wu ZH, Shi Y. When ubiquitin meets NF-kappaB: a trove for anti-cancer drug development. Curr Pharm Des. 2013;19(18):3263–75.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002;227(10):886–93.CrossRefGoogle Scholar
  72. 72.
    Lee A, Thurnham DI, Chopra M. Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma. Free Radic Biol Med. 2000;29(10):1051–5.CrossRefPubMedGoogle Scholar
  73. 73.
    Allen CM, Schwartz SJ, Craft NE, et al. Changes in plasma and oral mucosal lycopene isomer concentrations in healthy adults consuming standard servings of processed tomato products. Nutr Cancer. 2003;47(1):48–56.CrossRefPubMedGoogle Scholar
  74. 74.
    Kolberg M, Pedersen S, Bastani NE, et al. Tomato paste alters NF-kappaB and cancer-related mRNA expression in prostate cancer cells, xenografts, and xenograft microenvironment. Nutr Cancer. 2015;67(2):305–15.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Emelia A. Assar
    • 1
  • Magdalena Castellano Vidalle
    • 1
  • Mridula Chopra
    • 1
  • Sassan Hafizi
    • 1
  1. 1.Institute of Biomedical and Biomolecular Science (IBBS), School of Pharmacy and Biomedical SciencesUniversity of PortsmouthPortsmouthUK

Personalised recommendations