Skip to main content

Advertisement

SpringerLink
Log in

A novel compound, ferulic acid-bound resveratrol, induces the tumor suppressor gene p15 and inhibits the three-dimensional proliferation of colorectal cancer cells

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

Abstract

Resveratrol, a phytoalexin present in grapes and other edible foods, has been reported to have beneficial effects against various diseases including cancer. We previously reported that resveratrol and its derivative, caffeic acid-adducted resveratrol, selectively inhibit the three-dimensional (3D) proliferation of a human colorectal cancer cell line, HCT116 with activating KRAS mutation. Herein, we demonstrated that a novel compound, ferulic acid-bound resveratrol, also represses the 3D proliferation of HCT116 cells. We observed that resveratrol conjugated to two ferulic acids represses the 3D proliferation of HCT116 cells more strongly than resveratrol and resveratrol conjugated to one ferulic acid. Resveratrol conjugated to two ferulic acids also inhibited the 3D proliferation of MCF7 human breast cancer cells. We further uncovered that the resveratrol derivative increases the mRNA level of the tumor suppressor p15, a CDK inhibitor that functions as a brake of cell proliferation in HCT116 cells. These results imply that the resveratrol derivative represses 3D proliferation via increasing p15 expression in HCT116 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

References

  1. O’Brien LE, Zegers MM, Mostov KE (2002) Building epithelial architecture: insights from three-dimensional culture models. Nat Rev Mol Cell Biol 3:531–537. https://doi.org/10.1038/nrm859

    Article  CAS  PubMed  Google Scholar 

  2. Griffith LG, Swartz MA (2006) Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol 7:211–224. https://doi.org/10.1038/nrm1858

    Article  CAS  PubMed  Google Scholar 

  3. Tsunoda T, Takashima Y, Fujimoto T, Koyanagi M, Yoshida Y, Doi K, Tanaka Y, Kuroki M, Sasazuki T, Shirasawa S (2010) Three-dimensionally specific inhibition of DNA repair-related genes by activated KRAS in colon crypt model. Neoplasia 12(5):397–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mukherjee S, Dudley JI, Das DK (2010) Dose-dependency of resveratrol in providing health benefits. Dose Response 8:478–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Signorelli P, Ghidoni R (2005) Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16:449–466. https://doi.org/10.1016/j.jnutbio.2005.01.017

    Article  CAS  PubMed  Google Scholar 

  6. Carrizzo A, Forte M, Damato A, Trimarco V, Salzano F, Bartolo M, Maciag A, Puca AA, Vecchione C (2013) Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem Toxicol 61:215–226. https://doi.org/10.1016/j.fct.2013.07.021

    Article  CAS  PubMed  Google Scholar 

  7. Tsunoda T, Ishikura S, Doi K, Matsuzaki H, Iwaihara Y, Shirasawa S (2014) Resveratrol induces luminal apoptosis of human colorectal cancer HCT116 cells in three-dimensional culture. Anticancer Res 34(8):4551–4555

    CAS  PubMed  Google Scholar 

  8. Tsunoda T, Ishikura S, Doi K, Iwaihara Y, Hidesima H, Luo H, Hirose Y, Shirasawa S (2015) Establishment of a three-dimensional floating cell culture system for screening drugs targeting KRAS-mediated signaling molecules. Anticancer Res 35(8):4453–4459

    CAS  PubMed  Google Scholar 

  9. Okamoto H, Matsukawa T, Doi S, Tsunoda T, Sawata Y, Naemura M, Ohnuki K, Shirasawa S, Kotake Y (2018) A novel resveratrol derivative selectively inhibits the proliferation of colorectal cancer cells with KRAS mutation. Mol Cell Biochem 442(1–2):39–45

    Article  CAS  PubMed  Google Scholar 

  10. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512

    Article  CAS  PubMed  Google Scholar 

  11. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    Article  CAS  PubMed  Google Scholar 

  12. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260:85–88

    Article  CAS  PubMed  Google Scholar 

  13. Doi S, Kishi A, Matsukawa T, Nojima M, Matsui T, Yamada Y, Yamada I (2015) A novel resveratrol derivative. Japan. Patent 5703887

  14. Kishi A, Matsukawa T, Doi S, Nojima M, Matsui T, Yamada Y, Yamada I (2015) A novel resveratrol derivative. Japan. Patent 5673091

  15. Doi S, Matsukawa T, Kishi A, Nojima M, Matsui T, Yamada Y, Yamada I (2015) A novel resveratrol derivative. Japan. Patent 5728972

  16. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y (2007) pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes Dev 21:49–54. https://doi.org/10.1101/gad.1499407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kotake Y, Goto T, Naemura M, Inoue Y, Okamoto H, Tahara K (2017) Long noncoding RNA PANDA positively regulates proliferation of osteosarcoma cells. Anticancer Res 37:81–85. https://doi.org/10.21873/anticanres.11292

    Article  CAS  PubMed  Google Scholar 

  18. Janicke B, Hegardt C, Krogh M, Onning G, Akesson B, Cirenajwis HM, Oredsson SM (2011) The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells. Nutr Cancer 63:611–622. https://doi.org/10.1080/01635581.2011.538486

    Article  CAS  Google Scholar 

  19. Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257–261. https://doi.org/10.1038/371257a0

    Article  CAS  PubMed  Google Scholar 

  20. Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF (1999) Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem 274:35053–35058

    Article  CAS  PubMed  Google Scholar 

  21. Feng XH, Lin X, Derynck R (2000) Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. EMBO J 19:5178–5193. https://doi.org/10.1093/emboj/19.19.5178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, Xiong Y (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30:1956–1962. https://doi.org/10.1038/onc.2010.568

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Keishi Tamura and Haruna Okamoto for their helpful discussions and technical assistance. This work was supported by JSPS KAKENHI Grant Number 17K07184 (to YK) and the Naito Foundation (to YK). We thank Joe Barber Jr., PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Graduate School of Humanity-Oriented Science and Engineering, Kindai University, 11-6 Kayanomori, Iizuka, Fukuoka, 820-8555, Japan

    Yuuga Sawata, Nagisa Arikawa, Natsumi Matsunaga, Koichiro Ohnuki & Yojiro Kotake

  2. Department of Biological and Environmental Chemistry, Faculty of Humanity-Oriented Science and Engineering, Kindai University, 11-6 Kayanomori, Iizuka, Fukuoka, 820-8555, Japan

    Koichiro Ohnuki & Yojiro Kotake

  3. Technology Development Section, UHA Mikakuto Co., Ltd, 4-12 Kanzaki-cho, Chuo-ku, Osaka, 540-0016, Japan

    Taiji Matsukawa & Satoshi Doi

  4. Department of Cell Biology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Toshiyuki Tsunoda & Senji Shirasawa

  5. Central Research Institute for Advanced Molecular Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Toshiyuki Tsunoda & Senji Shirasawa

Authors
  1. Yuuga Sawata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taiji Matsukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoshi Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiyuki Tsunoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nagisa Arikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Natsumi Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koichiro Ohnuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Senji Shirasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yojiro Kotake
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yojiro Kotake.

Ethics declarations

Conflict of interest

The resveratrol derivatives (UHA023, UHA024, and UHA025) used in this study were provided by UHA Mikakuto Co., Ltd. Taiji Matsukawa and Satoshi Doi are employees of UHA Mikakuto Co., Ltd. The authors have no conflict of interest to declare.

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

Sawata, Y., Matsukawa, T., Doi, S. et al. A novel compound, ferulic acid-bound resveratrol, induces the tumor suppressor gene p15 and inhibits the three-dimensional proliferation of colorectal cancer cells. Mol Cell Biochem 462, 25–31 (2019). https://doi.org/10.1007/s11010-019-03606-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-019-03606-8

Keywords

Search

Navigation