Skip to main content

Advertisement

SpringerLink
Log in

Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Prostate cancer is the major health problem and the leading cause of male cancer death. Quercetin is a novel antitumor and antioxidant, whose molecular mechanism involved in cell cycle arrest in androgen independent prostate cancer cells remains unclear. In this study, we investigated the effects of quercetin on proliferation and cell cycle arrest by modulation of Cdc2/Cdk-1 protein in prostate cancer cells (PC-3). PC- 3 cells are human androgen independent cancer cells and were cultured with quercetin at concentrations of 50 and 100 μM for 24 h. Cell proliferation, apoptosis and cell cycle distribution were analyzed. Expression of Cdc2/Cdk-1, cyclin B1, cyclin A, p21/Cip1, pRb, pRb2/p130, Bcl-2, Bcl-XL, Bax and caspase-3 proteins were studied with western blot analysis. Addition of quercetin led to substantial decrease in the expression of Cdc2/Cdk-1, cyclin B1 and phosphorlyated pRb and increase in p21. Flowcytometric analysis showed that quercetin blocks G2-M transition, with significant induction of apoptosis. Apoptosis markers like Bcl-2 and Bcl-XL were significantly decreased and Bax and caspase-3 were increased. From this study, it was concluded that quercetin inhibits prostate cancer cell proliferation by altering the expression of cell cycle regulators and apoptotic proteins.

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

References

  • Agarwal R (2000) Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem Pharmacol 60:1051–1059

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Balabhadrapathruni S, Thomas TJ, Yurkow EJ, Amenta PS, Thomas T (2000) Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB-468 human breast cancer cells. Oncol Rep 7:3–12

    PubMed  CAS  Google Scholar 

  • Buchkovich K, Duffy LA, Harlow E (1989) The Retinoblastoma protein is phosphorlyated during specific phases of the cell cycle. Cell 58:1097–1105

    Article  PubMed  CAS  Google Scholar 

  • Casagrande F, Darbon JM (2001) Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem Pharmacol 61:1205–1215

    Article  PubMed  CAS  Google Scholar 

  • Catz SD, Johnson JL (2003) Bcl-2 in prostate cancer; a minireview. Apoptosis 8:29–37

    Article  PubMed  CAS  Google Scholar 

  • Choi JA, Kim JY, Lee JY, Kang CM, Kwon HJ, Yoo YD, Kim TW, Lee YS, Lee SJ (2001) Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol 19:837–844

    PubMed  CAS  Google Scholar 

  • Csokay B, Prajda N, Weber G, Olah E (1997) Molecular mechanisms in the antiproliferative action of quercetin. Life Sci 60:2157–2163

    Article  PubMed  CAS  Google Scholar 

  • Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245–2262

    PubMed  CAS  Google Scholar 

  • Ewen ME (1994) The cell cycle and the retinoblastoma protein family. Cancer Metastasis Rev 13:45–66

    Article  PubMed  CAS  Google Scholar 

  • Ferriola PC, Cody V, Middleton E Jr (1989) Protein-kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationship. Biochem Pharmacol 38:1617–1624

    Article  PubMed  CAS  Google Scholar 

  • Gali-Muhtasib H, Bakkar N (2002) Modulating cell cycle: current applications and prospects for future drug development. Curr Can Drug Targets 2:309–336

    Article  CAS  Google Scholar 

  • Gioeli D, Mandell JW, Petroni GR, Frierson Jr HF, Weber MJ (1999) Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 59:279–284

    PubMed  CAS  Google Scholar 

  • Grana X, Reddy P (1999) Cell cycle control in mammalian cells: role of cyclins, cyclin-dependent kinase (CDKs), growth-suppressor genes, cyclin-dependent kinase inhibitors (CDKIs). Oncogene 11:211–219

    Google Scholar 

  • Howard CM, Claudio PP, Luca AD, Stiegler P, Jori FP, Safdar NM, Caputi M, Khalili K, Giordano A (2000) Inducible pRb/p130 expression and growth-suppressive mechanisms: evidence of pRb130, p27kip1, and cyclin E negative feedback regulatory loop. Cancer Res 60:2737–2744

    PubMed  CAS  Google Scholar 

  • Knowles LM, Zigrossi DA, Tauber RA, Hightower C, Milner JA (2000) Flavonoids suppress androgen-independent human prostate tumor proliferation. Nutr Can 38:116–122

    Article  CAS  Google Scholar 

  • Lees JA, Buchkovich KJ, Marshak DR, Anderson CW, Harlow E (1991) The retinoblastoma protein is phosphorylated on multiple sites by human cdc2. EMBO J 10:4279–4290

    PubMed  CAS  Google Scholar 

  • Li X, Marami M, Yu J, Nan B, Roth JA, Kagawa S, Fang B, Dennerr L, Marcelli M (2001) Adenovirus-mediated Bax overexpression for the induction of therapeutic apoptosis in prostate cancer. Cancer Res 61:186–191

    PubMed  CAS  Google Scholar 

  • Lin BT-Y, Gruenwald S, Morla AO, Lee W-H, Wang JYJ (1991) Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase. EMBO J 10:857–864

    PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-phenol reagent. J Biol Chem 193:265–270

    PubMed  CAS  Google Scholar 

  • Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nature Rev Cancer 1:222–231

    Article  CAS  Google Scholar 

  • Martin JL, Pattison SL (2000) Insulin-like growth factor binding protein-3 is regulated by dihydrotestosterone and stimulates deoxyribonucleic acid synthesis and cell proliferation in LNCaP prostate carcinoma cell. Endocrinology 141:2401–2409

    Article  PubMed  CAS  Google Scholar 

  • Mittnacht S (1998) Control of pRB phosphorylation. Curr Opin Genet Dev 8:21–27

    Article  PubMed  CAS  Google Scholar 

  • Morgan DO (1995) Principles of CDK regulation. Nature 374:131–134

    Article  PubMed  CAS  Google Scholar 

  • Nguyen TT, Tran E, Nguyen TH, Do PT, Huynh TH, Huynh H (2004) The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis 25:647–659

    Article  PubMed  CAS  Google Scholar 

  • Paggi MG, Baldi A, Bonetto F, Giordano A (1996) Retinoblastoma protein family in cell cycle and cancer: a review. J Cell Biochem 62:418–430

    Article  PubMed  CAS  Google Scholar 

  • Paggi MG, Felson A, Giordano A (2003) Growth control by the retinoblastoma gene family. In: El Deiry WS (ed) Tumor suppressor genes (Vol 1). Humana Press, New Jersey, pp 3–19

  • Pavletich NP (1999) Mechanisms of cyclin-dependent kinase regulation: structures of cdks, their cyclin activators and Cip and INK4 inhibitors. J Mol Biol 287:821–828

    Article  PubMed  CAS  Google Scholar 

  • Quinn M, Babb P (2002) Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I. International comparisons. BJU Int 90:162–173

    Article  PubMed  CAS  Google Scholar 

  • Srivastava RK, Srivastava AR, Korsmeyers J, Nesterva M, Cho-chung YS, Longo DL (1998) Involvement of microtubules in the regulation of Bcl-2 phosphorylation and apoptosis through cyclic AMP-dependent kinase. Mol Cell Biol 18:3509–3517

    PubMed  CAS  Google Scholar 

  • Taraphdar AK, Roy M, Bhattacharya RK (2001) Natural products as inducers of apoptosis: implication for cancer therapy and prevention. Curr Sci 80:1387–1396

    CAS  Google Scholar 

  • Vijayababu MR, Kanagaraj P, Arunkumar A, Srinivasan N, Michael Aruldhas M, Arunakaran J (2004) Effects of quercetin on IGF system components in PC-3 cells. In: XXII symposium of the society for reproductive biology and comparative endocrinology (SRBCE), Chennai, pp 30–31

  • Wang S, DeGroff VL, Clinton SK (2003) Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. J Nutr 133:2367–2376

    PubMed  CAS  Google Scholar 

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704

    Article  PubMed  CAS  Google Scholar 

  • Yuan H, Pan Y, Young CY (2004) Overexpression of c-Jun induced by quercetin and resverol inhibits the expression and function of the androgen receptor in human prostate cancer cells. Cancer Lett 213(2):155–63

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Ion V. Deaciuc (University of Louisville, Kentucky, USA) for providing Bcl-2 and Bax antibodies and Prof. Franca Esposito (Universita’ di Napoli, Italy) for providing pRb antibody. We also thank Prof. Dhinakarraj, Animal Biotechnology, TANUVAS, Chennai, India for providing flowcytometry facility.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani campus, Chennai, 600 113, India

    M.R. Vijayababu, P. Kanagaraj, A. Arunkumar, R. Ilangovan, M.M. Aruldhas & J. Arunakaran

Authors
  1. M.R. Vijayababu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Kanagaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Arunkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Ilangovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M.M. Aruldhas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Arunakaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Arunakaran.

Additional information

This work was supported by grants from University Grants Commission (UGC award No. F.3.41 / 2002 (SR-II) dated 14-03-2002) to Dr. J. Arunakaran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vijayababu, M., Kanagaraj, P., Arunkumar, A. et al. Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. J Cancer Res Clin Oncol 131, 765–771 (2005). https://doi.org/10.1007/s00432-005-0005-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-005-0005-4

Keywords

Search

Navigation