Skip to main content
Springer Nature Link
Log in

The novel phospholipase C activator, m-3M3FBS, induces apoptosis in tumor cells through caspase activation, down-regulation of XIAP and intracellular calcium signaling

  • Original paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

See More

We investigated the effect of the novel phospholipase C activator, m-3M3FBS, on the apoptosis of human renal Caki cancer cells. Treatment with m-3M3FBS induced apoptosis of Caki cells, which was accompanied by accumulation of sub-G1 phase and DNA fragmentation. We found that induction of apoptosis is a common response of several cancer cell types to m-3M3FBS treatment. Overexpression of Bcl-2 and c-FLIPs fails to block m-3M3FBS-induced apoptosis. However, ectopic expression of XIAP partly inhibits m-3M3FBS-induced apoptosis in Caki cells. m-3M3FBS-induced apoptosis appeared to involve the XIAP down-regulation and caspase activation. m-3M3FBS also induced the expression of a potential proapoptotic gene, C/EBP homologous protein (CHOP), however, suppression of CHOP expression by small interfering RNA did not abrogate the m-3M3FBS-induced apoptosis. In addition, inhibition of phospholipase C (PLC) or chelation of intracellular calcium prevented m-3M3FBS-induced apoptosis in Caki cells, suggesting that the involvement of PLC pathway and intracellular calcium signaling on the apoptosis in m-3M3FBS-treated Caki cells. Collectively, our present results suggest that m-3M3FBS-induced apoptosis in Caki cells may result from the activation of caspase, down-regulation of XIAP and intracellular Ca2+ release pathway and that m-3M3FBS treatment might overcome the anti-apoptotic effect of Bcl-2 or c-FLIPs in cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

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
Fig. 7
Fig. 8

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Malaguarnera L (2004) Implications of apoptosis regulators in tumorigenesis. Cancer Metastasis Rev 23:367–387

    Article  PubMed  CAS  Google Scholar 

  2. Schulze-Bergkamen H, Krammer PH (2004) Apoptosis in cancer-implications for therapy. Semin Oncol 31:90–119

    Article  PubMed  CAS  Google Scholar 

  3. Hu W, Kavanagh JJ (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4:721–729

    Article  PubMed  CAS  Google Scholar 

  4. Li M, Zhang Z, Hill DL, Wang H, Zhang R (2007) Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res 67:1988–1996

    Article  PubMed  CAS  Google Scholar 

  5. Nottrott S, Schoentaube J, Genth H, Just I, Gerhard R (2007) Clostridium difficile toxin A-induced apoptosis is p53-independent but depends on glucosylation of Rho GTPases. Apoptosis 12:1443–1453

    Article  PubMed  CAS  Google Scholar 

  6. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308

    Article  PubMed  CAS  Google Scholar 

  7. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290

    Article  PubMed  CAS  Google Scholar 

  8. Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664

    Article  PubMed  CAS  Google Scholar 

  9. Debatin KM, Poncet D, Kroemer G (2002) Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene 21:8786–8803

    Article  PubMed  CAS  Google Scholar 

  10. Norbury CJ, Zhivotovsky B (2004) DNA damage-induced apoptosis. Oncogene 23:2797–2808

    Article  PubMed  CAS  Google Scholar 

  11. Ferreria CG, Epping M, Kruyt FAE, Giaccone G (2002) Apoptosis: target of cancer therapy. Clin Cancer Res 8:2024–2034

    Google Scholar 

  12. Richter C, Schlegel J, Schweizer M (1992) Prooxidant-induced Ca2+ release from liver mitochondria. Specific versus nonspecific pathways. Ann N Y Acad Sci 663:262–268

    Article  PubMed  CAS  Google Scholar 

  13. Jiang S, Chow SC, Nicotera P, Orrenius S (1994) Intracellular Ca2+ signals activate apoptosis in thymocytes: studies using the Ca(2+)-ATPase inhibitor thapsigargin. Exp Cell Res 212:84–92

    Article  PubMed  CAS  Google Scholar 

  14. Petersen A, Castilho RF, Hansson O, Wieloch T, Brundin P (2000) Oxidative stress, mitochondrial permeability transition and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neurons. Brain Res 857:20–29

    Article  PubMed  CAS  Google Scholar 

  15. Wu CC, Lin JP, Yang JS et al (2006) Capsaicin induced cell cycle arrest and apoptosis in human esophagus epidermoid carcinoma CE 81T/VGH cells through the elevation of intracellular reactive oxygen species and Ca2+ productions and caspase-3 activation. Mutat Res 601:71–82

    PubMed  CAS  Google Scholar 

  16. Harman AW, Maxwell MJ (1995) An evaluation of the role of calcium in cell injury. Annu Rev Pharmacol Toxicol 35:129–144

    Article  PubMed  CAS  Google Scholar 

  17. Bae YS, Lee TG, Park JC, Hur JH, Kim Y, Heo K, Kwak JY, Suh PG, Ryu SH (2003) Identification of a compound that directly stimulates phospholipase C activity. Mol Pharmacol 63:1043–1050

    Article  PubMed  CAS  Google Scholar 

  18. Lee YN, Lee HY, Kim JS, Park C, Choi YH, Lee TG, Ryu SH, Kwak JY, Bae YS (2005) The novel phospholipase C activator, m-3M3FBS, induces monocytic leukemia cell apoptosis. Cancer Lett 222:227–235

    Article  PubMed  CAS  Google Scholar 

  19. Wen J, You KR, Lee SY, Song CH, Kim DG (2002) Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem 277:38954–38964

    Article  PubMed  CAS  Google Scholar 

  20. Sheng-Tanner X, Bump EA, Hedley DW (1998) An oxidative stress-mediated death pathway in irradiated human leukemia cells mapped using multilaser flow cytometry. Radiat Res 150:636–647

    Article  PubMed  CAS  Google Scholar 

  21. Menon SG, Sarsour EH, Kalen AL et al (2007) Superoxide signaling mediates N-acetyl-L-cysteine-induced G1 arrest: regulatory role of cyclin D1 and manganese superoxide dismutase. Cancer Res 67:6392–6399

    Article  PubMed  CAS  Google Scholar 

  22. Kim R, Tanabe K, Emi M, Uchida Y, Toge T (2005) Modulation of tamoxifen sensitivity by antisense Bcl-2 and trastuzumab in breast carcinoma cells. Cancer 103:2199–2207

    Article  PubMed  CAS  Google Scholar 

  23. Voehringer DW, Meyn RE (1998) Reversing drug resistance in bcl-2-expressing tumor cells by depleting glutathione. Drug Resist Updat 1:345–351

    Article  PubMed  CAS  Google Scholar 

  24. Lee TJ, Kim EJ, Kim S et al (2006) Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells. Mol Cancer Ther 5:2398–2407

    Article  PubMed  CAS  Google Scholar 

  25. Matta H, Eby MT, Gazdar AF, Chaudhary PM (2002) Role of MRIT/cFLIP in protection against chemotherapy-induced apoptosis. Cancer Biol Ther 1:652–660

    PubMed  CAS  Google Scholar 

  26. Longley DB, Wilson TR, McEwan M et al (2006) c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene 25:838–848

    Article  PubMed  CAS  Google Scholar 

  27. Pyrko P, Kardosh A, Liu YT et al (2007) Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib. Mol Cancer Ther 6:1262–1275

    Article  PubMed  CAS  Google Scholar 

  28. Copanaki E, Schurmann T, Eckert A et al (2007) The amyloid precursor protein potentiates CHOP induction and cell death in response to ER Ca2+ depletion. Biochim Biophys Acta 1773:157–165

    Article  PubMed  CAS  Google Scholar 

  29. El-Sibai M, Backer JM (2007) Phospholipase C gamma negatively regulates Rac/Cdc42 activation in antigen-stimulated mast cells. Eur J Immunol 37:261–270

    Article  PubMed  CAS  Google Scholar 

  30. Kim JA, Kang YS, Lee YS (2005) A phospholipase C-dependent intracellular Ca2+ release pathway mediates the capsaicin-induced apoptosis in HepG2 human hepatoma cells. Arch Pharm Res 28:73–80

    Article  PubMed  CAS  Google Scholar 

  31. Noh DY, Shin SH, Rhee SG (1995) Phosphoinositide-specific phospholipase C and mitogenic signaling. Biochim Biophys Acta 1242:99–113

    PubMed  Google Scholar 

  32. Rhee SG, Bae YS (1997) Regulation of phosphoinositide-specific phospholipase C isozymes. J Biol Chem 272:15045–15048

    Article  PubMed  CAS  Google Scholar 

  33. Rhee SG (2001) Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70:281–312

    Article  PubMed  CAS  Google Scholar 

  34. Song Z, Yao X, Wu M (2003) Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem 278:23130–23140

    Article  PubMed  CAS  Google Scholar 

  35. Shi RX, Ong CN, Shen HM (2005) Protein kinase C inhibition and x-linked inhibitor of apoptosis protein degradation contribute to the sensitization effect of luteolin on tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cancer cells. Cancer Res 65:7815–7823

    Article  PubMed  CAS  Google Scholar 

  36. Sasaki H, Sheng Y, Kotsuji F, Tsang BK (2000) Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res 60:5659–5666

    PubMed  CAS  Google Scholar 

  37. Matsumiya T, Imaizumi T, Yoshida H, Kimura H, Satoh K (2001) Cisplatin inhibits the expression of X-chromosome-linked inhibitor of apoptosis protein in an oral carcinoma cell line. Oral Oncol 37:296–300

    Article  PubMed  CAS  Google Scholar 

  38. Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1:707–717

    PubMed  CAS  Google Scholar 

  39. Knuefermann C, Lu Y, Liu B et al (2003) HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22:3205–3212

    Article  PubMed  CAS  Google Scholar 

  40. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164

    Article  PubMed  CAS  Google Scholar 

  41. Westphal S, Kalthoff H (2003) Apoptosis: targets in pancreatic cancer. Mol Cancer 2:6

    Article  PubMed  Google Scholar 

  42. Gutierrez-Puente Y, Zapata-Benavides P, Tari AM, Lopez-Berestein G (2002) Bcl-2-related antisense therapy. Semin Oncol 29:71–6

    Article  PubMed  CAS  Google Scholar 

  43. Jonsson G, Paulie S, Grandien A (2003) High level of cFLIP correlates with resistance to death receptor-induced apoptosis in bladder carcinoma cells. Anticancer Res 23:1213–1218

    PubMed  Google Scholar 

  44. Natoni F, Diolordi L, Santoni C, Gilardini Montani MS (2005) Sodium butyrate sensitise human pancreatic cancer cells to both the intrinsic and the extrinsic apoptotic pathways. Biochim Biophys Acta 1745:318–329

    Article  PubMed  CAS  Google Scholar 

  45. Nicotera P, Bellomo G, Orrenius S (1992) Calcium-mediated mechanisms in chemically induced cell death. Annu Rev Pharmacol Toxicol 32:449–470

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the MRC program of the Korea Science & Engineering Foundation (KOSEF) (R13-2002-028-01002-0)

Author information

Authors and Affiliations

  1. Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu, 700-712, South Korea

    Eun Mi Jung, Tae-Jin Lee, Jong-Wook Park & Taeg Kyu Kwon

  2. Department of Biochemistry, College of Medicine, Dong-A University, Busan, 602-714, South Korea

    Yoe-Sik Bae

  3. Department of Pharmacology, School of Medicine, Kyungpook National University, Taegu, 700-422, South Korea

    Sang Hyun Kim

  4. Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, Korea

    Yung Hyun Choi

Authors
  1. Eun Mi Jung
    View author publications

    Search author on:PubMed Google Scholar

  2. Tae-Jin Lee
    View author publications

    Search author on:PubMed Google Scholar

  3. Jong-Wook Park
    View author publications

    Search author on:PubMed Google Scholar

  4. Yoe-Sik Bae
    View author publications

    Search author on:PubMed Google Scholar

  5. Sang Hyun Kim
    View author publications

    Search author on:PubMed Google Scholar

  6. Yung Hyun Choi
    View author publications

    Search author on:PubMed Google Scholar

  7. Taeg Kyu Kwon
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Taeg Kyu Kwon.

Additional information

Eun Mi Jung and Tae-Jin Lee contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

(PPT 71 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jung, E.M., Lee, TJ., Park, JW. et al. The novel phospholipase C activator, m-3M3FBS, induces apoptosis in tumor cells through caspase activation, down-regulation of XIAP and intracellular calcium signaling. Apoptosis 13, 133–145 (2008). https://doi.org/10.1007/s10495-007-0159-4

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s10495-007-0159-4

Keywords