Kahweol from Coffee Induces Apoptosis by Upregulating Activating Transcription Factor 3 in Human Colorectal Cancer Cells

  • Park, Gwang Hun (Department of Bioresource Sciences, Andong National University) ;
  • Song, Hun Min (Department of Bioresource Sciences, Andong National University) ;
  • Jeong, Jin Boo (Department of Bioresource Sciences, Andong National University)
  • Received : 2016.05.25
  • Accepted : 2016.08.23
  • Published : 2017.05.01


Kahweol as a coffee-specific diterpene has been reported to induce apoptosis in human cancer cells. Although some molecular targets for kahweol-mediated apoptosis have been elucidated, the further mechanism for apoptotic effect of kahweol is not known. Activating transcription factor 3 (ATF3) has been reported to be associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which kahweol stimulates ATF3 expression and apoptosis in human colorectal cancer cells. Kahweol increased apoptosis in human colorectal cancer cells. It also increased ATF3 expression through the transcriptional activity. The responsible cis-element for ATF3 transcriptional activation by kahweol was CREB located between -147 to -85 of ATF3 promoter. ATF3 overexpression increased kahweol-mediated cleaved PARP, while ATF3 knockdown attenuated the cleavage of PARP by kahweol. Inhibition of ERK1/2 and $GSK3{\beta}$ blocked kahweol-mediated ATF3 expression. The results suggest that kahweol induces apoptosis through ATF3-mediated pathway in human colorectal cancer cells.


Supported by : National Research Foundation of Korea (NRF)


  1. Baek, S .J., Kim, J. S., Jackson, F. R., Eling, T. E., McEntee, M. F. and Lee, S. H. (2004) Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. Carcinogenesis 25, 2425-2432.
  2. Bruning, A., Burger, P., Vogel, M., Rahmeh, M., Friese, K., Lenhard, M. and Burges, A. (2009) Bortezomib treatment of ovarian cancer cells mediates endoplasmic reticulum stress, cell cycle arrest, and apoptosis. Invest. New Drugs 27, 543-551.
  3. Cardenas, C., Quesada, A. R. and Medina, M. A. (2014) Insights on the antitumor effects of kahweol on human breast cancer: decreased survival and increased production of reactive oxygen species and cytotoxicity. Biochem. Biophys. Res. Commun. 447, 452-458.
  4. Cavin, C., Holzhaeuser, D., Scharf, G., Constable, A., Huber, W. W. and Schilter, B. (2002) Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem. Toxicol. 40, 1155-1163.
  5. Chae, J. I., Jeon, Y. J. and Shim, J. H. (2014) Anti-proliferative properties of kahweol in oral squamous cancer through the regulation specificity protein 1. Phytother. Res. 28, 1879-1886.
  6. Chen, H. H. and Wang, D. L. (2004) Nitric oxide inhibits matrix metalloproteinase-2 expression via the induction of activating transcription factor 3 in endothelial cells. Mol. Pharmacol. 65, 1130-1140.
  7. Cho, K. N., Sukhthankar, M., Lee, S. H., Yoon, J. H. and Baek, S. J. (2007) Green tea catechin (-)-epicatechin gallate induces tumour suppressor protein ATF3 via EGR-1 activation. Eur. J. Cancer 43, 2404-2412.
  8. Choi, D. W., Lim, M. S., Lee, J. W., Chun, W., Lee, S. H., Nam, Y. H., Park, J. M., Choi, D. H., Kang, C. D., Lee, S. J. and Park, S. C. (2015) The cytotoxicity of kahweol in HT-29 human colorectal cancer cells is mediated by apoptosis and suppression of heat shock protein 70 expression. Biomol. Ther. (Seoul) 23, 128-133.
  9. Giovannucci, E. (1998) Meta-analysis of coffee consumption and risk of colorectal cancer. Am. J. Epidemiol. 147, 1043-1052.
  10. Hai, T. and Hartman, M. G. (2001) The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene 273, 1-11.
  11. Kim, H. G., Hwang, Y. P. and Jeong, H. G. (2009) Kahweol blocks STAT3 phosphorylation and induces apoptosis in human lung adenocarcinoma A549 cells. Toxicol. Lett. 187, 28-34.
  12. Lee, K. A., Chae, J. I. and Shim, J. H. (2012) Natural diterpenes from coffee, cafestol and kahweol induce apoptosis through regulation of specificity protein 1 expression in human malignant pleural mesothelioma. J. Biomed. Sci. 19, 60.
  13. Lee, S. H., Bahn, J. H., Whitlock, N. C. and Baek, S. J. (2010) Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways. Oncogene 29, 5182-5192.
  14. Lee, S. H., Kim, J. S., Yamaguchi, K., Eling, T. E. and Baek, S. J. (2005) Indole-3-carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem. Biophys. Res. Commun. 328, 63-69.
  15. Lee, S. H., Yamaguchi, K., Kim, J. S., Eling, T. E., Safe, S., Park, Y. and Baek, S. J. (2006) Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner. Carcinogenesis 27, 972-981.
  16. Liang, G., Wolfgang, C. D., Chen, B. P., Chen, T. H. and Hai, T. (1996) ATF3 gene. Genomic organization, promoter, and regulation. J. Biol. Chem. 271, 1695-1701.
  17. Lu, D., Wolfgang, C. D. and Hai, T. (2006) Activating transcription factor 3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J. Biol. Chem. 281, 10473-10481.
  18. Saito, T., Abe, D. and Nogata, Y. (2015) Coffee diterpenes potentiate the cytolytic activity of KHYG-1 NK Leukemia cells. Food Sci. Technol. Res. 21, 281-284.
  19. St Germain, C., Niknejad, N., Ma, L., Garbuio, K., Hai, T. and Dimitroulakos, J. (2010) Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3. Neoplasia 12, 527-538.
  20. Um, H. J., Oh, J. H., Kim, Y. N., Choi, Y. H., Kim, S. H., Park, J. W. and Kwon, T. K. (2010) The coffee diterpene kahweol sensitizes TRAIL-induced apoptosis in renal carcinoma Caki cells through down-regulation of Bcl-2 and c-FLIP. Chem. Biol. Interact. 186, 36-42.
  21. Whitlock, N. C., Bahn, J. H., Lee, S. H., Eling, T. E. and Baek, S. J. (2011) Resveratrol-induced apoptosis is mediated by early growth response-1, Kruppel-like factor 4, and activating transcription factor 3. Cancer Prev. Res. (Phila) 4, 116-127.
  22. Yan, C., Lu, D., Hai, T. and Boyd, D. D. (2005) Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination. EMBO J. 24, 2425-2435.

Cited by

  1. ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression vol.37, pp.1, 2018,
  2. An insight towards anticancer potential of major coffee constituents vol.44, pp.4, 2018,
  3. Manzamine A Exerts Anticancer Activity against Human Colorectal Cancer Cells vol.16, pp.8, 2018,