Skip to main content

Advertisement

SpringerLink
Log in

Chelerythrine suppresses proliferation and metastasis of human prostate cancer cells via modulating MMP/TIMP/NF-κB system

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

Abstract

Chelerythrine is a natural benzo[c]phenanthridine alkaloid found in many herbs and displays a wide range of antitumor activities. Here, the present study tested their effects on prostate cancer cells. The addition of chelerythrine can significantly inhibit the proliferation of androgen-independent prostate cancer DU145 and PC-3 cells at the concentration of 5 and 10 μM, but not on androgen-dependent prostate cancer LNCaP cells as well as normal prostate epithelial cell line PrEC cells. Wound migration and transwell invasion assay showed the similar inhibitory effect of chelerythrine on the migration and invasion of DU145 and PC-3 cells in the same condition. Western blot analysis further confirmed that chelerythrine not only dramatically decreased MMP-2, MMP-9, and uPA protein expression, but also augmented the expression of their endogenous inhibitors (TIMP-1 and TIMP-2) and plasminogen activator inhibitors (PAI-1 and PAI-2) in both cancer cells. Meanwhile, NF-κB and AP-1 transcription factors were all suppressed as evidenced by the decline of p-p65, c-Fos, and c-Jun protein expression in both cells. Taken together, these findings suggested that chelerythrine could reduce the metastasis of androgen-independent prostate cancer cells via modulation of MMP/TIMP system and inactivation of NF-κB 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

Similar content being viewed by others

Abbreviations

ER:

Endoplasmic reticulum

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

FBS:

Fetal bovine serum

PrEC:

Prostate epithelial cells cell line

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamidegel electrophoresis

SD:

Standard deviation

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. De Wang X, Su GY, Zhao C, Qu FZ, Wang P, Zhao YQ (2018) Anticancer activity and potential mechanisms of 1C, a ginseng saponin derivative, on prostate cancer cells. J Ginseng Res 42:133–143. https://doi.org/10.1016/j.jgr.2016.12.014

    Article  PubMed  Google Scholar 

  3. Mirza MB, Elkady AI, Al-Attar AM, Syed FQ, Mohammed FA, Hakeem KR (2018) Induction of apoptosis and cell cycle arrest by ethyl acetate fraction of Phoenix dactylifera L. (Ajwa dates) in prostate cancer cells. J Ethnopharmacol 218:35–44. https://doi.org/10.1016/j.jep.2018.02.030

    Article  CAS  PubMed  Google Scholar 

  4. Beltran H, Jendrisak A, Landers M, Mosquera JM, Kossai M, Louw J et al (2016) The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer. Clin Cancer Res 22:1510–1519. https://doi.org/10.1158/1078-0432.CCR-15-0137

    Article  CAS  PubMed  Google Scholar 

  5. Koczurkiewicz P, Kowolik E, Podolak I, Wnuk D, Piska K, Łabędź-Masłowska A et al (2016) Synergistic cytotoxic and anti-invasive effects of mitoxantrone and triterpene saponins from Lysimachia ciliata on human prostate cancer cells. Planta Med 82:1546–1552. https://doi.org/10.1055/s-0042-117537

    Article  CAS  PubMed  Google Scholar 

  6. Huang SH, Tseng JC, Lin CY, Kuo YY, Wang BJ, Kao YH et al (2019) Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling. Phytomedicine 64:153068. https://doi.org/10.1016/j.phymed.2019.153068

    Article  CAS  PubMed  Google Scholar 

  7. Adsul P, Wray R, Spradling K, Darwish O, Weaver N, Siddiqui S (2015) Systematic review of decision aids for newly diagnosed prostate cancer patients making treatment decisions. J Urol 194:1247–1252. https://doi.org/10.1016/j.juro.2015.05.093

    Article  PubMed  Google Scholar 

  8. Tammela TL (2012) Endocrine prevention and treatment of prostate cancer. Mol Cell Endocrinol 360:59–67. https://doi.org/10.1016/j.mce.2012.03.002

    Article  CAS  PubMed  Google Scholar 

  9. Ryan CJ, Tindall DJ (2011) Androgen receptor rediscovered: the new biology and targeting the androgen receptor therapeutically. J Clin Oncol 29:3651–3658. https://doi.org/10.1200/JCO.2011.35.2005

    Article  CAS  PubMed  Google Scholar 

  10. Huang MY, Zhang LL, Ding J, Lu JJ (2018) Anticancer drug discovery from Chinese medicinal herbs. Chin Med 13:35. https://doi.org/10.1186/s13020-018-0192-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Malikova J, Zdarilova A, Hlobilkova A (2006) Effects of sanguinarine and chelerythrine on the cell cycle and apoptosis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 150:5–12. https://doi.org/10.5507/bp.2006.001

    Article  CAS  PubMed  Google Scholar 

  12. Zheng W, Qiu L, Wang R, Feng X, Han Y, Zhu Y et al (2015) Selective targeting of PPARγ by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency. Sci Rep. https://doi.org/10.1038/srep12222

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yang XJ, Miao F, Yao Y, Cao FJ, Yang R, Ma YN et al (2012) In vitro antifungal activity of sanguinarine and chelerythrine derivatives against phytopathogenic fungi. Molecules 17:13026–13035. https://doi.org/10.3390/molecules171113026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vrba J, Doležel P, Vičar J, Modrianský M, Ulrichová J (2008) Chelerythrine and dihydrochelerythrine induce G1 phase arrest and bimodal cell death in human leukemia HL-60 cells. Toxicol In Vitro 22:1008–1017. https://doi.org/10.1016/j.tiv.2008.02.007

    Article  CAS  PubMed  Google Scholar 

  15. Tang ZH, Cao WX, Wang ZY, Lu JH, Liu B, Chen X, Lu JJ (2017) Induction of reactive oxygen species-stimulated distinctive autophagy by chelerythrine in non-small cell lung cancer cells. Redox Biol 12:367–376. https://doi.org/10.1016/j.redox.2017.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu S, Yang Y, Li F, Huang L, Han Z, Wang G et al (2018) Chelerythrine induced cell death through ROS-dependent ER stress in human prostate cancer cells. Onco Targets Ther 11:2593. https://doi.org/10.2147/OTT.S157707

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wu B, Cui J, Zhang C, Li Z (2012) A polysaccharide from Agaricus blazei inhibits proliferation and promotes apoptosis of osteosarcoma cells. Int J Biol Macromol 50:1116–1120. https://doi.org/10.1016/j.ijbiomac.2012.02.023

    Article  CAS  PubMed  Google Scholar 

  18. Eisenbrand G, Pool-Zobel B, Baker V, Balls M, Blaauboer B, Boobis A et al (2002) Methods of in vitro toxicology. Food Chem Toxicol 40:193–236. https://doi.org/10.1016/S0278-6915(01)00118-1

    Article  CAS  PubMed  Google Scholar 

  19. Heo JC, Son M, Woo SU, Kweon M, Yoon EK, Lee HK et al (2008) A fraction of methylene chloride from Geum japonicum Thunberg inhibits tumor metastatic and angiogenic potential. Oncol Rep 19:1399–1403

    PubMed  Google Scholar 

  20. Zhang D, Liu H, Yang B, Hu J, Cheng Y (2019) L-securinine inhibits cell growth and metastasis of human androgen-independent prostate cancer DU145 cells via regulating mitochondrial and AGTR1/MEK/ERK/STAT3/PAX2 apoptotic pathways. Biosci Rep. https://doi.org/10.1042/BSR20190469

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  22. Manu KA, Kuttan G (2009) Anti-metastatic potential of Punarnavine, an alkaloid from Boerhaavia diffusa Linn. Immunobiology 214:245–255. https://doi.org/10.1016/j.imbio.2008.10.002

    Article  CAS  PubMed  Google Scholar 

  23. Park TY, Park MH, Shin WC, Rhee MH, Seo DW, Cho JY et al (2008) Anti-metastatic potential of ginsenoside Rp1, a novel ginsenoside derivative. Biol Pharm Bull 31:1802–1805. https://doi.org/10.1248/bpb.31.1802

    Article  CAS  PubMed  Google Scholar 

  24. Zell JA, Ou SH, Ziogas A, Anton-Culver H (2008) Cancer 112:136–143. https://doi.org/10.1002/cncr.23146

    Article  PubMed  Google Scholar 

  25. Wu HJ, Hao M, Yeo SK, Guan JL (2020) FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication. Oncogene 39:2539–2549. https://doi.org/10.1038/s41388-020-1162-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yilmaz M, Christofori G, Lehembre F (2007) Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med 13:535–541. https://doi.org/10.1016/j.molmed.2007.10.004

    Article  CAS  PubMed  Google Scholar 

  27. Hu XX, He PP, Qi GB, Gao YJ, Lin YX, Yang C et al (2017) Transformable nanomaterials as an artificial extracellular matrix for inhibiting tumor invasion and metastasis. ACS Nano 11:4086–4096. https://doi.org/10.1021/acsnano.7b00781

    Article  CAS  PubMed  Google Scholar 

  28. Deng JS, Chang JS, Liao JC, Chao W, Lee MM, Cheng CH et al (2018) Actinidia callosa var. callosa suppresses metastatic potential of human hepatoma cell SK-Hep1 by inhibiting matrix metalloproteinase-2 through PI3K/Akt and MAPK signaling pathways. Bot Stud 59:1–11. https://doi.org/10.1186/s40529-017-0216-4

    Article  CAS  Google Scholar 

  29. Sarwar MS, Zhang HJ, Tsang SW (2018) Perspectives of plant natural products in inhibition of cancer invasion and metastasis by regulating multiple signaling pathways. Curr Med Chem 25:5057–5087. https://doi.org/10.2174/0929867324666170918123413

    Article  CAS  PubMed  Google Scholar 

  30. Shan YF, Shen X, Xie YK, Chen JC, Shi HQ, Yu ZP et al (2009) Inhibitory effects of tanshinone II-A on invasion and metastasis of human colon carcinoma cells. Acta Pharmacol Sin 30:1537–1542. https://doi.org/10.1038/aps.2009.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hsu YL, Kuo PL, Cho CY, Ni WC, Tzeng TF, Ng LT et al (2007) Antrodia cinnamomea fruiting bodies extract suppresses the invasive potential of human liver cancer cell line PLC/PRF/5 through inhibition of nuclear factor κB pathway. Food Chem Toxicol 45:1249–1257. https://doi.org/10.1016/j.fct.2007.01.005

    Article  CAS  PubMed  Google Scholar 

  32. Bahassi EM, Karyala S, Tomlinson CR, Sartor MA, Medvedovic M, Hennigan RF (2004) Critical regulation of genes for tumor cell migration by AP-1. Clin Exp Metastasis 21:293–304. https://doi.org/10.1023/b:clin.0000046132.46946.dd

    Article  CAS  Google Scholar 

  33. Huang SF, Chu SC, Hsieh YH, Chen PN, Hsieh YS (2018) Viola yedoensis suppresses cell invasion by targeting the protease and NF-κB activities in A549 and Lewis lung carcinoma cells. Int J Med Sci 15:280. https://doi.org/10.7150/ijms.22793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baldwin AS (2001) Series introduction: the transcription factor NF-κB and human disease. J Clin Invest 107:3–6. https://doi.org/10.1172/JCI11891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ho ML, Chen PN, Chu SC, Kuo DY, Kuo WH, Chen JY et al (2010) Peonidin 3-glucoside inhibits lung cancer metastasis by downregulation of proteinases activities and MAPK pathway. Nutr Cancer 62:505–516. https://doi.org/10.1080/01635580903441261

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the Traditional Chinese Medicine Appropriate Technology Cultivation Project of Zhejiang Province (No: 2018ZT005) and Medical, Health Science and Technology Project of Zhejiang Province (No: 2019KY161).

Author information

Authors and Affiliations

  1. Department of Urological Surgery, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, 315010, China

    Binbin Yang, Dongxu Zhang, Junhai Qian & Yue Cheng

Authors
  1. Binbin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongxu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junhai Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BY and DZ conceived and designed the study. BY, DZ, JQ, and YC performed the experiments. JQ, and YC analyzed the data. BY and DZ wrote and reviewed the final manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Dongxu Zhang.

Ethics declarations

Conflict of interest

The authors declare that there are no competing interests associated with the manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, B., Zhang, D., Qian, J. et al. Chelerythrine suppresses proliferation and metastasis of human prostate cancer cells via modulating MMP/TIMP/NF-κB system. Mol Cell Biochem 474, 199–208 (2020). https://doi.org/10.1007/s11010-020-03845-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-03845-0

Keywords

Search

Navigation