Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells

Abstract

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21WAF1 and p27Kip1 CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21WAF1 appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-κB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

References

  • ACS. 2000 Cancer facts and figures American Cancer Society Inc.: Atlanta, GA

  • Bailey G, Selivonchick D, Hendricks J . 1987 Environ. Health Perspect. 71: 147–153

  • Beier RC . 1990 Rev. Environ. Contam. Toxicol. 113: 47–137

  • Biggs JR, Kraft AS . 1999 J. Biol. Chem. 274: 36987–36994

  • Biggs JR, Kudlow JE, Kraft AS . 1996 J. Biol. Chem. 271: 901–906

  • Bradfield CA, Bjeldanes LF . 1991 Adv. Exp. Med. Biol. 289: 153–163

  • Broadbent TA, Broadbent HS . 1998 Curr. Med. Chem. 5: 469–491

  • Cohen JH, Kristal AR, Stanford JL . 2000 J. Natl. Cancer Inst. 92: 61–68

  • Costello JF, Plass C, Arap W, Chapman VM, Held WA, Berger MS, Su Huang HJ, Cavenee WK . 1997 Cancer Res. 57: 1250–1254

  • Cover CM, Hsieh SJ, Tran SH, Hallden G, Kim GS, Bjeldanes LF, Firestone GL . 1998 J. Biol. Chem. 273: 3838–3847

  • Cram EJ, Garcia HH, Cover CM, Bjeldanes LF, Firestone GL . 2000 American Association of Cancer Research 91 San Francisco, CA p. 10

    Google Scholar 

  • Darmon AJ, Nicholson DW, Bleackley RC . 1995 Nature 377: 446–448

  • Dashwood RH . 1998 Chem. Biol. Interact. 110: 1–5

  • Dashwood RH, Arbogast DN, Fong AT, Pereira C, Hendricks JD, Bailey GS . 1989 Carcinogenesis 10: 175–181

  • Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF . 1995a Proc. Natl. Acad. Sci. USA 92: 5545–5549

  • Datto MB, Yu Y, Wang XF . 1995b J. Biol. Chem. 270: 28623–28628

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Gartel AL, Serfas MS, Gartel M, Goufman E, Wu GS, el-Deiry WS, Tyner AL . 1996 Exp. Cell. Res. 227: 171–181

  • Ge X, Yannai S, Rennert G, Gruener N, Fares FA . 1996 Biochem. Biophys. Res. Commun. 228: 153–158

  • Grubbs CJ, Steele VE, Casebolt T, Juliana MM, Eto I, Whitaker LM, Dragnev KH, Kelloff GJ, Lubet RL . 1995 Anticancer Res. 15: 709–716

  • Guo D, Schut HA, Davis CD, Snyderwine EG, Bailey GS, Dashwood RH . 1995 Carcinogenesis 16: 2931–2937

  • Huang P, Ballal K, Plunkett W . 1997 Cancer Res. 57: 3407–3414

  • Huber WW, McDaniel LP, Kaderlik KR, Teitel CH, Lang NP, Kadlubar FF . 1997 Mutat. Res. 376: 115–122

  • Katdare M, Osborne MP, Telang NT . 1998 Oncol. Rep. 5: 311–315

  • Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet RA, Doody LA, Malone WF, Hawk ET, Sigman CC . 1996 J. Cell. Biochem. Suppl. 26: 1–28

  • Kim DJ, Han BS, Ahn B, Hasegawa R, Shirai T, Ito N, Tsuda H . 1997 Carcinogenesis 18: 377–381

  • Kojima T, Tanaka T, Mori H . 1994 Cancer Res. 54: 1446–1449

  • Kolonel LN, Hankin JH, Whittemore AS, Wu AH, Gallagher RP, Wilkens LR, John EM, Howe GR, Dreon DM, West DW, Paffenbarger Jr RS . 2000 Cancer Epidemiol. Biomarkers Prev. 9: 795–804

  • Krongrad A, Lai S, Vidal EM . 1998 Semin. Urol. Oncol. 16: 30–34

  • Liu M, Iavarone A, Freedman LP . 1996a J. Biol. Chem. 271: 31723–31728

  • Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP . 1996b Genes Dev. 10: 142–153

  • Lukas J, Bartkova J, Rohde M, Strauss M, Bartek J . 1995a Mol. Cell. Biol. 15: 2600–2611

  • Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J . 1995b Nature 375: 503–506

  • Michnovicz JJ, Adlercreutz H, Bradlow HL . 1997 J. Natl. Cancer Inst. 89: 718–723

  • Missero C, Calautti E, Eckner R, Chin J, Tsai LH, Livingston DM, Dotto GP . 1995 Proc. Natl. Acad. Sci. USA 92: 5451–5455

  • Niwa T, Swaneck G, Bradlow HL . 1994 Steroids 59: 523–527

  • Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM . 1994 Nature 372: 570–573

  • Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M . 1995 Mol. Cell. Biol. 15: 2612–2624

  • Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge SJ . 1995 Science 267: 1024–1027

  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A . 1994a Genes Dev. 8: 9–22

  • Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J . 1994b Cell 78: 59–66

  • Safe SH . 1995 Environ. Health Perspect. 103: 346–351

  • Sakr WA, Grignon DJ, Haas GP, Schomer KL, Heilbrun LK, Cassin BJ, Powell J, Montie JA, Pantes JE, Crissman JD . 1995 Pathol. Res. Pract. 191: 838–841

  • Salomons GS, Brady HJ, Verwijs-Janssen M, Van Den Berg JD, Hart AA, Van Den Berg H, Behrendt H, Hahlen K, Smets LA . 1997 Int. J. Cancer 71: 959–965

  • Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ . 1995 Proc. Natl. Acad. Sci. USA 92: 7834–7838

  • Sherr CJ . 1994 Cell 79: 551–555

  • Sherr CJ, Roberts JM . 1995 Genes Dev. 9: 1149–1163

  • Slingerland JM, Hengst L, Pan CH, Alexander D, Stampfer MR, Reed SI . 1994 Mol. Cell. Biol. 14: 3683–3694

  • Steinmetz KA, Potter JD . 1996 J. Am. Diet. Assoc. 96: 1027–1039

  • Teixeira C, Pratt MA . 1997 Mol. Endocrinol. 11: 1191–1202

  • Telang NT, Katdare M, Bradlow HL, Osborne MP, Fishman J . 1997 Proc. Soc. Exp. Biol. Med. 216: 246–252

  • Timmermann S, Hinds PW, Munger K . 1997 Cell Growth Differ. 8: 361–370

  • Tiwari RK, Guo L, Bradlow HL, Telang NT, Osborne MP . 1994 J. Natl. Cancer Inst. 86: 126–131

  • Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . 1996 Science 274: 787–789

  • Wang CY, Mayo MW, Baldwin Jr AS . 1996 Science 274: 784–787

  • Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP . 1997 J. Cell. Biochem. Suppl. 29: 111–116

  • Xu M, Bailey AC, Hernaez JF, Taoka CR, Schut HA, Dashwood RH . 1996 Carcinogenesis 17: 1429–1434

Download references

Acknowledgements

This work was partly funded by the George Puschelberg Foundation and we sincerely thank the Foundation for its support. We also sincerely thank Ms Patricia Arlauskas for her editorial assistance.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chinni, S., Li, Y., Upadhyay, S. et al. Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 20, 2927–2936 (2001). https://doi.org/10.1038/sj.onc.1204365

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204365

Keywords

  • G1 cell cycle arrest
  • apoptosis
  • Indole-3-Carbinol (I3C)
  • prostate cancer (PCa)

This article is cited by

Search

Quick links