Skip to main content
SpringerLink
Log in

The flavonoid casticin enhances TRAIL-induced apoptosis of colon cancer cells through endoplasmic reticulum stress-mediated up-regulation of DR5

  • Published:
The Chinese-German Journal of Clinical Oncology

Abstract

Objective

The aim of this study was to explore the mechanisms by which the flavonoid casticin enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in colon cancer cells.

Methods

Human colon cancer HT-29 cells were treated with TRAIL or casticin. Cytotoxicity was examined by MTT assay, and apoptosis determined by morphological observation and flow cytometric analysis. Death receptor 5 (DR5), DR4, and endoplasmic reticulum (ER) stress response markers, including glucose regulating protein 78 (GRP78), activating transcription factor 4 (ATF4) and CHOP (CCAAT/enhancer binding protein homologous protein), were examined with western blot. Small interfering RNA (siRNA) transfection was employed to knock down CHOP.

Results

HT-29 cells were resistance to TRAIL-induced apoptosis, but casticin, at subtoxic concentrations, potentiated HT-29 cells to TRAIL-induced apoptosis. Casticin up-regulated the expression of DR5 time- and dose-dependent manners, but had no effect on the expression of DR4. Also, casticin increased the levels of ER stress response markers (GRP78, ATF4 and CHOP) in a similar way to DR5. Knockdown of CHOP by specific siRNA, or salubrinal, an ER stress inhibitor, abolished the up-regulation of DR5 and enhancement of TRAIL-induced apoptosis by casticin.

Conclusion

Casticin enhances TRAIL-induced apoptosis of colon cancer cells by ER stress-mediated up-regulation of DR5.

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

Similar content being viewed by others

References

  1. Ge RL, Shen F, Wu MC. Expression of TRAIL receptors in human hepatocellular carcinoma and apoptosis induced by TRAIL. Chinese-German J Clin Oncol, 2003, 2: 140–144.

    Article  Google Scholar 

  2. Mellier G, Huang S, Shenoy K, et al. TRAILing death in cancer. Mol Aspects Med, 2010, 31: 93–112.

    Article  PubMed  CAS  Google Scholar 

  3. Zhang L, Fang B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther, 2005, 12: 228–237.

    Article  PubMed  CAS  Google Scholar 

  4. Tang SY, Zhong MZ, Yuan GJ, et al. Casticin, a flavonoid, potentiates TRAIL-induced apoptosis through modulation of anti-apoptotic proteins and death receptor 5 in colon cancer cells. Oncol Rep, 2013, 29: 474–480.

    PubMed  CAS  Google Scholar 

  5. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol, 2011, 54: 795–809.

    Article  PubMed  CAS  Google Scholar 

  6. Jing G, Wang JJ, Zhang SX. ER stress and apoptosis: a new mechanism for retinal cell death. Exp Diabetes Res, 2012, 2012: 589–589.

    Article  Google Scholar 

  7. Cao JG, Peng SP, Sun L, et al. Vascular basement membrane-derived multifunctional peptide, a novel inhibitor of angiogenesis and tumor growth. Acta Biochim Biophys Sin (Shanghai), 2006, 38: 514–521.

    Article  CAS  Google Scholar 

  8. Yang XH, Zheng X, Cao JG, et al. 8-Bromo-7-methoxychrysin-induced apoptosis of hepatocellular carcinoma cells involves ROS and JNK. World J Gastroenterol, 2010, 16: 3385–3393.

    Article  PubMed  CAS  Google Scholar 

  9. Jung EM, Lim JH, Lee TJ, et al. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis, 2005, 26: 1905–1913.

    Article  PubMed  CAS  Google Scholar 

  10. Prasad S, Ravindran J, Sung B, et al. Garcinol potentiates TRAILinduced apoptosis through modulation of death receptors and antiapoptotic proteins. Mol Cancer Ther, 2010, 9: 856–868.

    Article  PubMed  CAS  Google Scholar 

  11. Sung B, Ravindran J, Prasad S, et al. Gossypol induces death receptor-5 through activation of the ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. J Biol Chem, 2010, 285: 35418–35427.

    Article  PubMed  CAS  Google Scholar 

  12. Haïdara K, Zamir L, Shi QW, et al. The flavonoid Casticin has multiple mechanisms of tumor cytotoxicity action. Cancer Lett, 2006, 242: 180–190.

    Article  PubMed  Google Scholar 

  13. Csupor-Löffler B, Hajdú Z, Zupkó I, et al. Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines. Phytother Res, 2009, 23: 672–676.

    Article  PubMed  Google Scholar 

  14. Wang M, Wey S, Zhang Y, et al. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal, 2009, 11: 2307–2316.

    Article  PubMed  CAS  Google Scholar 

  15. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ, 2004, 11: 381–389.

    Article  PubMed  CAS  Google Scholar 

  16. Chen LH, Jiang CC, Kiejda KA, et al. Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response. Carcinogenesis, 2007, 28: 2328–2336.

    Article  PubMed  CAS  Google Scholar 

  17. Rieger J, Frank B, Weller M, et al. Mechanisms of resistance of human glioma cells to Apo2 ligand/TNF-related apoptosis-inducing ligand. Cell Physiol Biochem, 2007, 20: 23–34.

    Article  PubMed  CAS  Google Scholar 

  18. Kurbanov BM, Fecker LF, Geilen CC, et al. Resistance of melanoma cells to TRAIL does not result from upregulation of antiapoptotic proteins by NF-kappaB but is related to downregulation of initiator caspases and DR4. Oncogene, 2007, 26: 3364–3377.

    Article  PubMed  CAS  Google Scholar 

  19. Kim H, Kim EH, Eom YW, et al. Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5. Cancer Res, 2006, 66: 1740–1750.

    Article  PubMed  CAS  Google Scholar 

  20. Ohtsuki T, Kikuchi H, Koyano T, et al. Death receptor 5 promoterenhancing compounds isolated from Catimbium speciosum and their enhancement effect on TRAIL-induced apoptosis. Bioorg Med Chem, 2009, 17: 6748–6754.

    Article  PubMed  CAS  Google Scholar 

  21. Yang JF, Cao JG, Tian L, et al. 5, 7-Dimethoxyflavone sensitizes TRAIL-induced apoptosis through DR5 upregulation in hepatocellular carcinoma cells. Cancer Chemother Pharmacol, 2012, 69: 195–206.

    Article  PubMed  CAS  Google Scholar 

  22. Yang J, Yang Y, Tian L, et al. Casticin-induced apoptosis involves death receptor 5 upregulation in hepatocellular carcinoma cells. World J Gastroenterol, 2011, 17: 4298–4307.

    Article  PubMed  CAS  Google Scholar 

  23. Wu GS, Burns TF, McDonald ER 3rd, et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet, 1997, 17: 141–143.

    Article  PubMed  CAS  Google Scholar 

  24. Ravi R, Bedi GC, Engstrom LW, et al. Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB. Nat Cell Biol, 2001, 3: 409–416.

    Article  PubMed  CAS  Google Scholar 

  25. Zou W, Liu X, Yue P, et al. PPARgamma ligands enhance TRAIL-induced apoptosis through DR5 upregulation and c-FLIP downregulation in human lung cancer cells. Cancer Biol Ther, 2007, 6: 99–106.

    Article  PubMed  CAS  Google Scholar 

  26. Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem, 2004, 279: 45495–45502.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, The First Affiliated Hospital of Nanhua University, Hengyang, 421001, China

    Sanyuan Tang, Zhengyang Yu, Leilan Yin & Hao Jiang

  2. Cancer Hospital of Chongqing Qianjiang National Hospital, Chongqing, 409000, China

    Guangjin Yuan

Authors
  1. Sanyuan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guangjin Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengyang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leilan Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanyuan Tang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tang, S., Yuan, G., Yu, Z. et al. The flavonoid casticin enhances TRAIL-induced apoptosis of colon cancer cells through endoplasmic reticulum stress-mediated up-regulation of DR5. Chin. -Ger. J. Clin. Oncol. 12, 279–284 (2013). https://doi.org/10.1007/s10330-013-1180-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10330-013-1180-4

Key words

Search

Navigation