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Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer DU145 cells via inactivation of the p38 MAPK signaling pathway

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Abstract

Acacetin (5,7-dihydroxy-4′-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. The effect of acacetin on antimetastasis in human prostate cancer DU-145 cells was investigated. First, the result demonstrated acacetin could exhibit an inhibitory effect on the abilities of the adhesion, invasion, and migration by cell–matrix adhesion assay, wound-healing assay, and Boyden chamber assay. Data also showed acacetin could inhibit the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) involved in the downregulation of the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels. Next, acacetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-κB), c-Fos, and c-Jun. Also, the treatment with acacetin to DU145 cells also leads to a dose-dependent inhibition on the binding ability of NF-κB and activator protein-1 (AP-1). Furthermore, the treatment of inhibitors specific for p38 MAPK (SB203580) to DU145 cells could cause reduced expressions of MMP-2, MMP-9, and u-PA. These results showed acacetin could inhibit the invasion and migration abilities of DU145 cells by reducing MMP-2, MMP-9, and u-PA expressions through suppressing p38 MAPK signaling pathway and inhibiting NF-κB- or AP-1-binding activity. These findings proved acacetin might be offered further application as an antimetastatic agent.

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Abbreviations

MMPs:

Matrix metalloproteinases

u-PA:

Urokinase-type plasminogen activator

ECM:

Extracellular matrix

ERK:

Extracellular signal-regulated kinase

JNK/SAPK:

c-Jun N-terminal kinase/stress-activated protein kinase

p38 MAPK:

p38 Mitogen-activated protein kinase

PI3K:

Phosphoinositide 3-kinase

NF-κB:

Nuclear factor kappa B

AP-1:

Activator protein-1

IκB:

Inhibitor of NF-κB

References

  1. Greenlee RT, Murray T, Bolden S, Wingo PA (2000) Cancer statistics. CA Cancer J Clin 50:7–33

    Article  CAS  PubMed  Google Scholar 

  2. Yim D, Singh RP, Agarwal C, Lee S, Chi H, Agarwal R (2005) A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells. Cancer Res 65:1035–1044

    Article  CAS  PubMed  Google Scholar 

  3. Sandberg L, Papareddy P, Silver J, Bergh A, Mei YF (2009) Replication-competent Ad11p vector (RCAd11p) efficiently transduces and replicates in hormone-refractory metastatic prostate cancer cells. Hum Gene Ther 20:361–373

    Article  CAS  PubMed  Google Scholar 

  4. Kraft C, Jenett-Siems K, Siems K, Jakupovic J, Mavi S, Bienzle U, Eich E (2003) In vitro antiplasmodial evaluation of medicinal plants from Zimbabwe. Phytother Res 17:123–128

    Article  CAS  PubMed  Google Scholar 

  5. Pan MH, Lai CS, Wang YJ, Ho CT (2006) Acacetin suppressed LPS-induced up-expression of iNOS and COX-2 in murine macrophages and TPA-induced tumor promotion in mice. Biochem Pharmacol 72:1293–1303

    Article  CAS  PubMed  Google Scholar 

  6. Yin Y, Gong FY, Wu XX, Sun Y, Li YH, Chen T, Xu Q (2008) Anti-inflammatory and immunosuppressive effect of flavones isolated from Artemisia vestita. J Ethnopharmacol 120:1–6

    Article  CAS  PubMed  Google Scholar 

  7. Hsu YL, Kuo PL, Lin CC (2004) Acacetin inhibits the proliferation of HepG2 by blocking cell cycle progression and inducing apoptosis. Biochem Pharmacol 67:823–829

    Article  CAS  PubMed  Google Scholar 

  8. Hsu YL, Kuo PL, Liu CF, Lin CC (2004) Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells. Cancer Lett 212:53–60

    Article  CAS  PubMed  Google Scholar 

  9. Pan MH, Lai CS, Hsu PC, Wang YJ (2005) Acacetin induces apoptosis in human gastric carcinoma cells accompanied by activation of caspase cascades and production of reactive oxygen species. J Agric Food Chem 53:620–630

    Article  CAS  PubMed  Google Scholar 

  10. Shim HY, Park JH, Paik HD, Nah SY, Kim DS, Han YS (2007) Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria- mediated death signaling and SAPK/JNK1/2-c-Jun activation. Mol Cells 24:95–104

    CAS  PubMed  Google Scholar 

  11. Singh RP, Agrawal P, Yim D, Agarwal C, Agarwal R (2005) Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: structure-activity relationship with linarin and linarin acetate. Carcinogenesis 26:845–854

    Article  CAS  PubMed  Google Scholar 

  12. Weiss L (1990) Metastatic inefficiency. Adv Cancer Res 54:159–211

    Article  CAS  PubMed  Google Scholar 

  13. Huang SC, Ho CT, Lin-Shiau SY, Lin JK (2005) Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun. Biochem Pharmacol 69:221–232

    Article  CAS  PubMed  Google Scholar 

  14. Bernhard EJ, Gruber SB, Muschel RJ (1994) Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci USA 91:4293–4297

    Article  CAS  PubMed  Google Scholar 

  15. Duffy MJ, Duggan C (2004) The urokinase plasminogen activator system: a rich source of tumour markers for the individualized management of patients with cancer. Clin Biochem 37:541–548

    Article  CAS  PubMed  Google Scholar 

  16. Itoh Y, Nagase H (2002) Matrix metalloproteinases in cancer. Essays Biochem 38:21–36

    CAS  PubMed  Google Scholar 

  17. Chan-Hui PY, Weaver R (1998) Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Biochem J 336:599–609

    CAS  PubMed  Google Scholar 

  18. Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2:289–300

    Article  CAS  PubMed  Google Scholar 

  19. Chen PN, Hsieh YS, Chiou HL, Chu SC (2005) Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways. Chem Biol Interact 156:141–150

    Article  CAS  PubMed  Google Scholar 

  20. Kwon GT, Cho HJ, Chung WY, Park KK, Moon A, Park JH (2008) Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling. J Nutr Biochem (in press)

  21. Lee SJ, Park SS, Lee US, Kim WJ, Moon SK (2008) Signaling pathway for TNF-alpha -induced MMP-9 expression: mediation through p38 MAP kinase, and inhibition by anti-cancer molecule magnolol in human urinary bladder cancer 5637 cells. Int Immunopharmacol 8:1821–1826

    Article  CAS  PubMed  Google Scholar 

  22. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494

    Article  CAS  PubMed  Google Scholar 

  23. Sliva D (2004) Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr Cancer Drug Targets 4:327–336

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 269:199–225

    Article  CAS  PubMed  Google Scholar 

  26. Jiang J, Grieb B, Thyagarajan A, Sliva D (2008) Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-kappaB signaling. Int J Mol Med 21:577–584

    CAS  PubMed  Google Scholar 

  27. Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS (2007) Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochem Biophys Res Commun 354:165–171

    Article  CAS  PubMed  Google Scholar 

  28. Hoppe-Seyler F, Butz K, Rittmuller C, von Knebel Doeberitz M (1991) A rapid microscale procedure for the simultaneous preparation of cytoplasmic RNA, nuclear DNA binding proteins and enzymatically active luciferase extracts. Nucleic Acids Res 19:5080

    Article  CAS  PubMed  Google Scholar 

  29. Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3:489–501

    Article  CAS  PubMed  Google Scholar 

  30. Turner NA, Aley PK, Hall KT, Warburton P, Galloway S, Midgley L, O’regan DJ, Wood IC, Ball SG, Porter KE (2007) Simvastatin inhibits TNFalpha-induced invasion of human cardiac myofibroblasts via both MMP-9-dependent and -independent mechanisms. J Mol Cell Cardio 43:168–176

    Article  CAS  Google Scholar 

  31. Aquilina JW, Lipsky JJ, Bostwick DG (1999) Androgen deprivation as a strategy for prostate cancer chemoprevention. J Natl Cancer Inst 89:689–696

    Article  Google Scholar 

  32. Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, Chung J (2001) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 15:1953–1962

    Article  CAS  PubMed  Google Scholar 

  33. Kleiner DE, Stetler-Stevenson WG (1999) Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 43:S42–S51

    Article  CAS  PubMed  Google Scholar 

  34. Stetler-Stevenson WG, Aznavoorian S, Liotta LA (1993) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 9:541–573

    Article  CAS  PubMed  Google Scholar 

  35. Gum R, Lengyel E, Juarez J, Chen JH, Sato H, Seiki M, Boyd D (1996) Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences. J Biol Chem 271:10672–10680

    Article  CAS  PubMed  Google Scholar 

  36. Hung SH, Shen KH, Wu CH, Liu CL, Shih YW (2009) α-Mangostin suppresses PC-3 human prostate carcinoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen activator expression through the JNK signaling pathway. J Agric Food Chem 57:1291–1298

    Article  CAS  PubMed  Google Scholar 

  37. Rothhammer T, Hahne JC, Florin A, Poser I, Soncin F, Wernert N, Bosserhoff AK (2004) The Ets-1 transcription factor is involved in the development and invasion of malignant melanoma. Cell Mol Life Sci 61:118–128

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the grant from the Subsidized Project of the Chung Hwa University, Tainan, Taiwan (97-HT-08008).

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Authors and Affiliations

  1. Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan

    Kun-Hung Shen, Shun-Hsing Hung & Chein-Liang Liu

  2. Department of Childhood Education and Nursery, Chia Nan University of Pharmacy and Science, Tainan, 717, Taiwan

    Kun-Hung Shen

  3. Department of Urology, Taipei Medical University, Taipei, 110, Taiwan

    Kun-Hung Shen

  4. Department of Biological Science and Technology, Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, Tainan, 717, Taiwan

    Li-Te Yin & Yuan-Wei Shih

  5. Department of Medical Technology, Kuo General Hospital, Tainan, 700, Taiwan

    Chun-Shui Huang

  6. Department of Neurology, Kuo General Hospital, Tainan, 700, Taiwan

    Chang-Hung Chao

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  1. Kun-Hung Shen
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Correspondence to Yuan-Wei Shih.

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Shen, KH., Hung, SH., Yin, LT. et al. Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer DU145 cells via inactivation of the p38 MAPK signaling pathway. Mol Cell Biochem 333, 279–291 (2010). https://doi.org/10.1007/s11010-009-0229-8

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  • DOI: https://doi.org/10.1007/s11010-009-0229-8

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