Skip to main content

Advertisement

SpringerLink
Log in

Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines

  • Research Article
  • Published:
Tumor Biology

Abstract

Studies on genetic changes underlying prostate cancer and the possible signaling pathways are getting increased day by day, and new treatment methods are being searched for. The aim of the present study is to investigate the effects of ferulic acid (FA), a phenolic compound, on cell cycle, apoptosis, invasion, and colony formation in the PC-3 and LNCaP prostate cancer cells. The effect of FA on cell viability was determined via a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method. Total RNA was isolated with Tri Reagent. Expression of 84 genes for both cell cycle and apoptosis separately was evaluated by reverse transcriptase PCR (RT-PCR). Protein expressions were evaluated by Western blot analysis. Furthermore, apoptotic effects of FA were observed with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Effects of FA on cell invasion and colony formation were determined using Matrigel chamber and colony assay, respectively. The half maximal inhibitory concentration (IC50) dose of FA was found to be 300 μM in PC-3 cells and 500 μM in LNCaP cells. According to RT-PCR results, it was observed that FA inhibited cell proliferation by increasing the gene expressions of ATR, ATM, CDKN1A, CDKN1B, E2F4, RB1, and TP53 and decreasing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 in PC-3 cells. On the other hand, it was seen that FA suppressed cell proliferation by increasing in the gene expressions of CASP1, CASP2, CASP8, CYCS, FAS, FASLG, and TRADD and decreasing in the gene expressions of BCL2 and XIAP in LNCaP cells. In this study, protein expression of CDK4 and BCL2 genes significantly decreased in these cells. It could induce apoptosis in PC-3 and LNCaP cells. Also, it was observed that FA suppressed the invasion in PC-3 and LNCaP cells. Moreover, it suppressed the colony formation. In conclusion, it has been observed that FA may lead to cell cycle arrest in PC-3 cells while it may cause apoptosis in LNCaP cells.

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

Similar content being viewed by others

Abbreviations

FA:

Ferulic acid

CDK:

Cyclin-dependent kinase

DMSO:

Dimethyl sulfoxide

XTT:

2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide

TUNEL:

Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling

AR:

Androgen receptor

References

  1. Szliszka E, Krol W. Polyphenols isolated from propolis augment TRAIL-induced apoptosis in cancer cells. Evid Based Complement Alternat Med. 2011. doi:10.1155/2013/731940.

    PubMed  PubMed Central  Google Scholar 

  2. Cimino S, Sortino G, Favilla V, Castelli T, Madonia M, Sansalone S, et al. Polyphenols: key issues involved in chemoprevention of prostate cancer. Oxid Med Cell Longev. 2012. doi:10.1155/2012/632959.

    PubMed  PubMed Central  Google Scholar 

  3. Chin JL, Reiter RE. Molecular markers and prostate cancer prognosis. Clin Prostate Cancer. 2004;3(3):157–64.

    Article  CAS  PubMed  Google Scholar 

  4. Velcheti V, Karnik S, Bardot SF, Prakash O. Pathogenesis of prostate cancer: lessons from basic research. Ochsner J. 2008;8(4):213–8.

    PubMed  PubMed Central  Google Scholar 

  5. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320–8.

    Article  PubMed  Google Scholar 

  6. Fresco P, Borges F, Diniz C, Marques MP. New insights on the anticancer properties of dietary polyphenols. Med Res Rev. 2009;26(6):747–66.

    Article  Google Scholar 

  7. Fresco P, Borges F, Marques MP, Diniz C. The anticancer properties of dietary polyphenols and its relation with apoptosis. Curr Pharm Des. 2010;16(1):114–34.

    Article  CAS  PubMed  Google Scholar 

  8. Huang WY, Cai YZ, Zhang Y. Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention. Nutr Cancer. 2010;62(1):1–20.

    Article  PubMed  Google Scholar 

  9. D’Archivio M, Filesi C, Di Benedetto R, Gargiulo R, Giovannini C, Masella R. Polyphenols, dietary sources and bioavailability. Ann Ist Super Sanita. 2007;43(4):348–61.

    PubMed  Google Scholar 

  10. Clifford MN. Chlorogenic acids and other cinnamates—nature, occurrence and dietary burden. J Sci Food Agric. 1999;79:362–72.

    Article  CAS  Google Scholar 

  11. Carbone C, Campisi A, Musumeci T, Raciti G, Bonfanti R, Puglisi G. FA-loaded lipid drug delivery systems: preparation, characterization and biological studies. Eur J Pharm Sci. 2014;52:12–20.

    Article  CAS  PubMed  Google Scholar 

  12. Janicke B, Hegardt C, Krogh M, Onning G, Akesson B, Cirenajwis HM, et al. The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells. Nutr Cancer. 2011;63(4):611–22.

    Article  CAS  PubMed  Google Scholar 

  13. Knudsen KE, Arden KC, Cavenee WK. Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells. J Biol Chem. 1998;273(32):20213–22.

    Article  CAS  PubMed  Google Scholar 

  14. Balk SP and Knudsen KE. AR, the cell cycle, and prostate cancer. Nucl Recept Signal. 2008; doi: 10.1621/nrs.06001

  15. Xu Y, Chen SY, Ross KN, Balk SP. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and posttranscriptional increases in cyclin D proteins. Cancer Res. 2006;66(15):7783–92.

    Article  CAS  PubMed  Google Scholar 

  16. Brooks JD, Bova GS, Isaacs WB. Allelic loss of the retinoblastoma gene in primary human prostatic adenocarcinomas. Prostate. 1995;26(1):35–9.

    Article  CAS  PubMed  Google Scholar 

  17. Ittmann MM, Wieczorek R. Alterations of the retinoblastoma gene in clinically localized, stage B prostate adenocarcinomas. Hum Pathol. 1996;27(1):28–34.

    Article  CAS  PubMed  Google Scholar 

  18. Tricoli JV, Gumerlock PH, Yao JL, Chi SG, D’Souza SA, Nestok BR, et al. Alterations of the retinoblastoma gene in human prostate adenocarcinoma. Genes Chromosomes Cancer. 1996;15(2):108–14.

    Article  CAS  PubMed  Google Scholar 

  19. Jarrard DF, Modder J, Fadden P, Fu V, Sebree L, Heisey D, et al. Alterations in the p16/pRb cell cycle checkpoint occur commonly in primary and metastatic human prostate cancer. Cancer Lett. 2002;185(2):191–9.

    Article  CAS  PubMed  Google Scholar 

  20. Peng CC, Chyau CC, Wang HE, Chang CH, Chen KC, Chou KY, et al. Cytotoxicity of Ferulic acid on T24 cell line differentiated by different microenvironments. BioMed Res Int. 2013. doi:10.1155/2013/579859.

    Google Scholar 

  21. Hemaiswarya S, Doble M. Combination of phenylpropanoids with 5-fluorouracil as anti-cancer agents against human cervical cancer (HeLa) cell line. Phytomedicine. 2013;20(2):151–8.

    Article  CAS  PubMed  Google Scholar 

  22. Cho SD, Li G, Hu H, Jiang C, Kang KS, Lee YS, et al. Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells. Nutr Cancer. 2005;52(2):213–24.

    Article  CAS  PubMed  Google Scholar 

  23. Karanika S, Karantanos T, Li L, Corn PG, Thompson TC. DNA damage response and prostate cancer: defects, regulation and therapeutic implications. Oncogene. 2014. doi:10.1038/onc.2014.238.

    PubMed  PubMed Central  Google Scholar 

  24. Hou Y, Yang J, Zhao G, Yuan Y. Ferulic acid inhibits endothelial cell proliferation through NO downregulating ERK1/2 pathway. J Cell Biochem. 2004;93(6):1203–9.

    Article  CAS  PubMed  Google Scholar 

  25. Dong Q, Meng P, Wang T, Qin W, Wang F, Yuan J, et al. MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS One. 2010;5(4):e10147.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Susaki E, Nakayama K, Nakayama KI. Cyclin D2 translocates p27 out of the nucleus and promotes its degradation at the G0-G1 transition. Mol Cell Biol. 2007;27(13):4626–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nikoleishvili D, Pertia A, Trsintsadze O, Gogokhia N, Managadze L, Chkhotua A. Expression of p27(Kip1), cyclin D3 and Ki67 in BPH, prostate cancer and hormone-treated prostate cancer cells. Int Urol Nephrol. 2008;40(4):953–9.

    Article  CAS  PubMed  Google Scholar 

  28. D’Angiolella V, Donato V, Vijayakumar S, Saraf A, Florens L, Washburn MP, et al. SCF(cyclin F) controls centrosome homeostasis and mitotic fidelity via CP110 degradation. Nature. 2010;466(7302):138–42.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zieske JD. Expression of cyclin-dependent kinase inhibitors during corneal wound repair. Prog Retin Eye Res. 2000;19(3):257–70.

    Article  CAS  PubMed  Google Scholar 

  30. Sirma H, Broemel M, Stumm L, Tsourlakis T, Steurer S, Tennstedt P, et al. Loss of CDKN1B/p27Kip1 expression is associated with ERG fusion-negative prostate cancer, but is unrelated to patient prognosis. Oncol Lett. 2013;6(5):1245–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR. The E2F transcription factor is a cellular target for the Rb protein. Cell. 1991;65(6):1053–62.

    Article  CAS  PubMed  Google Scholar 

  32. Plesca D, Crosby ME, Gupta D, Almasan A. E2F4 function in G2: maintaining G2-arrest to prevent mitotic entry with damaged DNA. Cell Cycle. 2007;6(10):1147–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nagata S. Apoptosis by death factor. Cell. 1997;88(3):355–65.

    Article  CAS  PubMed  Google Scholar 

  34. Chinnadurai G, Vijayalingam S, Rashmi R. BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes. Oncogene. 2008;27(1):20–9.

    Article  Google Scholar 

  35. Bandagula VR, Prasad NR. 2-Deoxy-glucose and ferulic acid modulates radiation response signaling in non-small cell lung cancer cells. Tumour Biol. 2013;34(1):251–9.

    Article  Google Scholar 

  36. Guo Y, Kyprianou N. Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis. Cancer Res. 1999;59(6):1366–71.

    CAS  PubMed  Google Scholar 

  37. Winter RN, Kramer A, Borkowski A, Kyprianou N. Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. Cancer Res. 2001;61(3):1227–32.

    CAS  PubMed  Google Scholar 

  38. VanOosten RL, Earel Jr JK, Griffith TS. Histone deacetylase inhibitors enhance Ad5-TRAIL killing of TRAIL-resistant prostate tumor cells through increased caspase-2 activity. Apoptosis. 2007;12(3):561–71.

    Article  CAS  PubMed  Google Scholar 

  39. Kampa M, Alexaki VI, Notas G, Nifli AP, Nistikaki A, Hatzoglou A, et al. Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: potential mechanisms of action. Breast Cancer Res. 2004;6(2):63–74.

    Article  Google Scholar 

  40. Krajewska M, Krajewski S, Banares S, Huang X, Turner B, Bubendorf L, et al. Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res. 2003;9(13):4914–25.

    CAS  PubMed  Google Scholar 

  41. Ramp U, Krieg T, Caliskan E, Mahotka C, Ebert T, Willers R, et al. XIAP expression is an independent prognostic marker in clear-cell renal carcinomas. Hum Pathol. 2004;35(8):1022–8.

    Article  CAS  PubMed  Google Scholar 

  42. Karthikeyan S, Kanimozhi G, Prasad NR, Mahalakshmi R. Radiosensitizing effect of ferulic acid on human cervical carcinoma cells in vitro. Toxicol In Vitro. 2011;25(7):1366–75.

    Article  CAS  PubMed  Google Scholar 

  43. Tsai CM, Yen GC, Sun FM, Yang SF, Weng CJ. Assessment of the anti-invasion potential and mechanism of select cinnamic acid derivatives on human lung adenocarcinoma cells. Mol Pharm. 2013;10(5):1890–900.

    Article  CAS  PubMed  Google Scholar 

  44. Fang HY, Wang HM, Chang KF, Hu HT, Hwang LJ, Fu TF, et al. Feruloyl-L-arabinose attenuates migration, invasion and production of reactive oxygen species in H1299 lung cancer cells. Food ChemToxicol. 2013;58:459–66. doi:10.1016/j.fct.2013.05.019.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was produced from the MSc thesis of Canan Eroglu and supported by Instructor Training Program.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Medical Biology, Faculty of Meram Medicine, Konya Necmettin Erbakan University, Konya, Turkey

    Canan Eroğlu

  2. Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, Turkey

    Mücahit Seçme, Gülseren Bağcı & Yavuz Dodurga

Authors
  1. Canan Eroğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mücahit Seçme
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gülseren Bağcı
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yavuz Dodurga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yavuz Dodurga.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

Table S1

(DOCX 20 kb)

Table S2

(DOCX 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eroğlu, C., Seçme, M., Bağcı, G. et al. Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines. Tumor Biol. 36, 9437–9446 (2015). https://doi.org/10.1007/s13277-015-3689-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3689-3

Keywords

Search

Navigation