Skip to main content

Advertisement

SpringerLink
Log in

Indomethacin promotes apoptosis in gastric cancer cells through concomitant degradation of Survivin and Aurora B kinase proteins

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

Abstract

Regular usage of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced incidence of a variety of cancers. The molecular mechanisms underlying these chemopreventive effects remain poorly understood. This current investigation showed that in gastric cancer cells: (1) Indomethacin treatment enhanced the degradation of chromosomal passenger proteins, Survivin and Aurora B kinase; (2) Indomethacin treatment down-regulated Aurora B kinase activity in a cell cycle-independent fashion; (3) siRNA knockdown of Survivin level promoted Aurora B kinase protein degradation, and vice versa; (4) ectopic overexpression of Survivin blocked reduction of Aurora B kinase level and activity by indomethacin treatment, and vice versa; (5) siRNA knockdown of Aurora B kinase level and AZD1152 inhibition of its activity induced apoptosis, and overexpression of Aurora B kinase inhibited indomethacin-induced apoptosis; (6) indomethacin treatment reduced Aurora B kinase level, coinciding with reduction of Survivin level and induction of apoptosis, in KATO III and HT-29 cells, and in mouse gastric mucosa. A role for Aurora B kinase function in NSAID-induced apoptosis was not previously explored. Thus this report provides better understanding of the molecular mechanisms underlying the anti-cancer effect of NSAIDs by elucidating a significant role for Aurora B kinase in indomethacin-induced apoptosis.

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
Fig. 6

Similar content being viewed by others

References

  1. Gurpinar E, Grizzle WE, Piazza GA (2013) COX-independent mechanisms of cancer chemoprevention by anti-inflammatory drugs. Front Oncol 3:181. doi:10.3389/fonc.2013.00181

    Article  PubMed Central  PubMed  Google Scholar 

  2. Farrugia G, Balzan R (2013) The proapoptotic effect of traditional and novel nonsteroidal anti-inflammatory drugs in Mammalian and yeast cells. Oxid Med Cell Longev 2013:504230. doi:10.1155/2013/504230

    Article  PubMed Central  PubMed  Google Scholar 

  3. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921

    Article  CAS  PubMed  Google Scholar 

  4. Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J, Altieri DC (1998) Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152:43–49

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Lehner R, Enomoto T, McGregor JA, Shroyer L, Haugen BR, Pugazhenthi U, Shroyer KR (2002) Correlation of survivin mRNA detection with histologic diagnosis in normal endometrium and endometrial carcinoma. Acta Obstet Gynecol Scand 81:162–167

    Article  PubMed  Google Scholar 

  6. Ka H, Hunt JS (2003) Temporal and spatial patterns of expression of inhibitors of apoptosis in human placentas. Am J Pathol 163:413–422

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Chiou SK, Moon WS, Jones MK, Tarnawski AS (2003) Survivin expression in the stomach: implications for mucosal integrity and protection. Biochem Biophys Res Commun 305:374–379

    Article  CAS  PubMed  Google Scholar 

  8. Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook BP, Dufault MR, Ferguson AT, Gao Y, He TC, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K et al (1999) Analysis of human transcriptomes. Nat Genet 23:387–388

    Article  CAS  PubMed  Google Scholar 

  9. Lee GH, Joo YE, Koh YS, Chung IJ, Park YK, Lee JH, Kim HS, Choi SK, Rew JS, Park CS, Kim SJ (2006) Expression of survivin in gastric cancer and its relationship with tumor angiogenesis. Eur J Gastroenterol Hepatol 18:957–963

    Article  CAS  PubMed  Google Scholar 

  10. Song KY, Jung CK, Park WS, Park CH (2009) Expression of the antiapoptosis gene Survivin predicts poor prognosis of stage III gastric adenocarcinoma. Jpn J Clin Oncol 39:290–296

    Article  PubMed  Google Scholar 

  11. Tu SP, Jiang XH, Lin MC, Cui JT, Yang Y, Lum CT, Zou B, Zhu YB, Jiang SH, Wong WM, Chan AO, Yuen MF, Lam SK, Kung HF, Wong BC (2003) Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. Cancer Res 63:7724–7732

    CAS  PubMed  Google Scholar 

  12. Deveraux QL, Reed JC (1999) IAP family proteins–suppressors of apoptosis. Genes Dev 13:239–252

    Article  CAS  PubMed  Google Scholar 

  13. Carmena M, Wheelock M, Funabiki H, Earnshaw WC (2012) The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol 13:789–803. doi:10.1038/nrm3474

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Vader G, Kauw JJ, Medema RH, Lens SM (2006) Survivin mediates targeting of the chromosomal passenger complex to the centromere and midbody. EMBO Rep 7:85–92

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT (2002) Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosphorylation. Mol Biol Cell 13:3064–3077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chu Y, Yao PY, Wang W, Wang D, Wang Z, Zhang L, Huang Y, Ke Y, Ding X, Yao X (2011) Aurora B kinase activation requires survivin priming phosphorylation by PLK1. J Mol Cell Biol 3:260–267. doi:10.1093/jmcb/mjq037

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Crosio C, Fimia GM, Loury R, Kimura M, Okano Y, Zhou H, Sen S, Allis CD, Sassone-Corsi P (2002) Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol 22:874–885

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Wheatley SP, Henzing AJ, Dodson H, Khaled W, Earnshaw WC (2004) Aurora-B phosphorylation in vitro identifies a residue of survivin that is essential for its localization and binding to inner centromere protein (INCENP) in vivo. J Biol Chem 279:5655–5660

    Article  CAS  PubMed  Google Scholar 

  19. Bishop JD, Schumacher JM (2002) Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the Aurora B kinase stimulates Aurora B kinase activity. J Biol Chem 277:27577–27580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ban R, Matsuzaki H, Akashi T, Sakashita G, Taniguchi H, Park SY, Tanaka H, Furukawa K, Urano T (2009) Mitotic regulation of the stability of microtubule plus-end tracking protein EB3 by ubiquitin ligase SIAH-1 and Aurora mitotic kinases. J Biol Chem 284:28367–28381. doi:10.1074/jbc.M109.000273

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Portella G, Passaro C, Chieffi P (2011) Aurora B: a new prognostic marker and therapeutic target in cancer. Curr Med Chem 18:482–496

    Article  CAS  PubMed  Google Scholar 

  22. Diaz RJ, Golbourn B, Shekarforoush M, Smith CA, Rutka JT (2012) Aurora kinase B/C inhibition impairs malignant glioma growth in vivo. J Neurooncol 108:349–360. doi:10.1007/s11060-012-0835-2

    Article  CAS  PubMed  Google Scholar 

  23. Chiou SK, Tanigawa T, Akahoshi T, Abdelkarim B, Jones MK, Tarnawski AS (2005) Survivin: a novel target for indomethacin-induced gastric injury. Gastroenterology 128:63–73

    Article  CAS  PubMed  Google Scholar 

  24. Chiou SK, Mandayam S (2007) NSAIDs enhance proteasomic degradation of survivin, a mechanism of gastric epithelial cell injury and apoptosis. Biochem Pharmacol 74:1485–1495

    Article  CAS  PubMed  Google Scholar 

  25. Chiou SK, Hodges A, Hoa N (2010) Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury. J Pharmacol Exp Ther 334:693–702

    Article  CAS  PubMed  Google Scholar 

  26. Mima S, Tsutsumi S, Ushijima H, Takeda M, Fukuda I, Yokomizo K, Suzuki K, Sano K, Nakanishi T, Tomisato W, Tsuchiya T, Mizushima T (2005) Induction of claudin-4 by nonsteroidal anti-inflammatory drugs and its contribution to their chemopreventive effect. Cancer Res 65:1868–1876

    Article  CAS  PubMed  Google Scholar 

  27. Bonin AM, Yáñez JA, Fukuda C, Teng XW, Dillon CT, Hambley TW, Lay PA, Davies NM (2010) Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats. Cancer Chemother Pharmacol 66:755–764

    Article  CAS  PubMed  Google Scholar 

  28. Chiou SK, Hoa N, Hodges A (2011) Sulindac sulfide induces autophagic death in gastric epithelial cells via survivin down-regulation: a mechanism of NSAIDs-induced gastric injury. Biochem Pharmacol 81:1317–1323

    Article  CAS  PubMed  Google Scholar 

  29. Tarnawski A, Pai R, Chiou SK, Chai J, Chu EC (2005) Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. Biochem Biophys Res Commun 334:207–212

    Article  CAS  PubMed  Google Scholar 

  30. Mortlock AA, Foote KM, Heron NM, Jung FH, Pasquet G, Lohmann JJ, Warin N, Renaud F, De Savi C, Roberts NJ, Johnson T, Dousson CB, Hill GB, Perkins D, Hatter G, Wilkinson RW, Wedge SR, Heaton SP, Odedra R, Keen NJ, Crafter C, Brown E, Thompson K, Brightwell S, Khatri L, Brady MC, Kearney S, McKillop D, Rhead S, Parry T, Green S (2007) Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase. J Med Chem 50:2213–2224

    Article  CAS  PubMed  Google Scholar 

  31. Hadj-Slimane R, Pamonsinlapatham P, Herbeuval JP, Garbay C, Lepelletier Y, Raynaud F (2010) RasV12 induces Survivin/Aurora B pathway conferring tumor cell apoptosis resistance. Cell Signal 22:1214–1221

    Article  CAS  PubMed  Google Scholar 

  32. van der Waal MS, Hengeveld RC, van der Horst A, Lens SM (2012) Cell division control by the chromosomal passenger complex. Exp Cell Res 318:1407–1420

    Article  PubMed  Google Scholar 

  33. Cimini D, Wan X, Hirel CB, Salmon ED (2006) Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol 16:1711–1718

    Article  CAS  PubMed  Google Scholar 

  34. Lampson MA, Renduchitala K, Khodjakov A, Kapoor TM (2004) Correcting improper chromosome-spindle attachments during cell division. Nat Cell Biol 6:232–237

    Article  CAS  PubMed  Google Scholar 

  35. Manchado E, Guillamot M, Malumbres M (2012) Killing cells by targeting mitosis. Cell Death Differ 19:369–377

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by a Department of Veterans Administration Merit Review Grant, and by SCIRE Small grant to S.-K.C.

Author information

Authors and Affiliations

  1. Department of Veterans Affairs Medical Center, 5901 E 7th st., Long Beach, CA, 90822-5201, USA

    Shiun-Kwei Chiou, Neil Hoa, Amy Hodges, Lishen Ge & Martin R. Jadus

  2. Department of Medicine, University of California, 101 The City Drive, Irvine, Orange, CA, 92868, USA

    Shiun-Kwei Chiou

  3. UCI Pathology Department, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, 92697, USA

    Martin R. Jadus

  4. Neuro-Oncology Program, Chao Comprehensive Cancer Center, UC Irvine School of Medicine, University of California, Irvine, Orange, CA, 92868, USA

    Martin R. Jadus

Authors
  1. Shiun-Kwei Chiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil Hoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amy Hodges
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lishen Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin R. Jadus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiun-Kwei Chiou.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chiou, SK., Hoa, N., Hodges, A. et al. Indomethacin promotes apoptosis in gastric cancer cells through concomitant degradation of Survivin and Aurora B kinase proteins. Apoptosis 19, 1378–1388 (2014). https://doi.org/10.1007/s10495-014-1002-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-014-1002-3

Keywords

Search

Navigation