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Licensed Unlicensed Requires Authentication Published by De Gruyter February 24, 2020

Polyamine stimulation perturbs intracellular Ca2+ homeostasis and decreases viability of breast cancer BT474 cells

Louis W.C. Chow , Kar-Lok Wong , Lian-Ru Shiao , King-Chuen Wu EMAIL logo and Yuk-Man Leung EMAIL logo

Abstract

Intracellular polyamines such as spermine and spermidine are essential to cell growth in normal and especially in cancer cells. However, whether extracellular polyamines affect cancer cell survival is unknown. We therefore examined the actions of extracellular polyamines on breast cancer BT474 cells. Our data showed that spermine, spermidine, and putrescine decreased cell viability by apoptosis. These polyamines also elicited Ca2+ signals, but the latter were unlikely triggered via Ca2+-sensing receptor (CaSR) as BT474 cells have been demonstrated previously to lack CaSR expression. Spermine-elicited Ca2+ response composed of both Ca2+ release and Ca2+ influx. Spermine caused a complete discharge of the cyclopiazonic acid (CPA)-sensitive Ca2+ pool and, expectedly, endoplasmic reticulum (ER) stress. The Ca2+ influx pore opened by spermine was Mn2+-impermeable, distinct from the CPA-triggered store-operated Ca2+ channel, which was Mn2+-permeable. Spermine cytotoxic effects were not due to oxidative stress, as spermine did not trigger reactive oxygen species formation. Our results therefore suggest that spermine acted on a putative polyamine receptor in BT474 cells, causing cytotoxicity by Ca2+ overload, Ca2+ store depletion, and ER stress.

Acknowledgments

Y.M.L. would like to thank China Medical University, Taiwan, for providing funding (CMU108-S-31, CMU107-S-01). L.W.C.C. would like to thank the Macau Science and Technology Development Fund (FUNDO PARA O DESENVOLVIMENTO DAS CIÊNCIAS E DA TECNOLOGIA) for support (grant number 002/2015/A1). K.C.W. thanks the Chang Gung Memorial Hospital, Chiayi, for support (CMRPG6J0371, CMRPG6G0541).

  1. Conflict of interests: The authors declare no conflict of interests.

  2. Ethical approval: No humans or animals were used in this study; only cell lines were used in this work, and therefore, ethical approval is not required.

References

1. Murray-Stewart TR, Woster PM, Casero RA, Jr. Targeting polyamine metabolism for cancer therapy and prevention. Biochem J 2016;473:2937–53.10.1042/BCJ20160383Search in Google Scholar

2. Pegg AE. S-Adenosylmethionine decarboxylase. Essays Biochem 2009;46:25–46.10.1042/bse0460003Search in Google Scholar

3. Read GW, Hong SM, Kiefer EF. Competitive inhibition of 48/80-induced histamine release by benzalkonium chloride and its analogs and the polyamine receptor in mast cells. J Pharmacol Exp Ther 1982;222:652–7.Search in Google Scholar

4. Geibel JP. The calcium-sensing receptor. J Nephrol 2010;Suppl 16:S130–5.Search in Google Scholar

5. Williams K, Romano C, Dichter MA, Molinoff PB. Modulation of the NMDA receptor by polyamines. Life Sci 1991;48:469–98.10.1016/0024-3205(91)90463-LSearch in Google Scholar

6. Guerra GP, Rubin MA, Mello CF. Modulation of learning and memory by natural polyamines. Pharmacol Res 2016;112:99–118.10.1016/j.phrs.2016.03.023Search in Google Scholar

7. Stefanelli C, Bonavita F, Stanic’ I, Mignani M, Facchini A, Pignatti C, et al. Spermine causes caspase activation in leukaemia cells. FEBS Lett 1998;437:233–6.10.1016/S0014-5793(98)01239-3Search in Google Scholar

8. Facchiano F, D’Arcangelo D, Riccomi A, Lentini A, Beninati S, Capogrossi MC. Transglutaminase activity is involved in polyamine-induced programmed cell death. Exp Cell Re. 2001;271:118–29.10.1006/excr.2001.5356Search in Google Scholar PubMed

9. Leung YM, Huang CF, Chao CC, Lu DY, Kuo CS, Cheng TH, et al. Voltage-gated K+ channels play a role in cAMP-stimulated neuritogenesis in mouse neuroblastoma N2A cells. J Cell Physiol 2011;226:1090–8.10.1002/jcp.22430Search in Google Scholar PubMed

10. Lu DY, Tang CH, Yeh WL, Wong KL, Lin CP, Chen YH, et al. SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. Eur J Pharmacol 2009;613:146–54.10.1016/j.ejphar.2009.03.001Search in Google Scholar PubMed

11. Chen CY, Hour MJ, Lin WC, Wong KL, Shiao LR, Cheng KS, et al. Antagonism of Ca2+-sensing receptors by NPS 2143 is transiently masked by p38 activation in mouse brain bEND.3 endothelial cells. Naunyn Schmiedebergs Arch Pharmacol 2019;392:823–32.10.1007/s00210-019-01637-ySearch in Google Scholar PubMed

12. Fukuchi J, Hiipakka RA, Kokontis JM, Nishimura K, Igarashi K, Liao S. TATA-binding protein-associated factor 7 regulates polyamine transport activity and polyamine analog-induced apoptosis. J Biol Chem 2004;279:29921–9.10.1074/jbc.M401078200Search in Google Scholar PubMed

13. Sala-Rabanal M, Li DC, Dake GR, Kurata HT, Inyushin M, Skatchkov SN, et al. Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm 2013;10:1450–8.10.1021/mp400024dSearch in Google Scholar PubMed PubMed Central

14. He Y, Kashiwagi K, Fukuchi J, Terao K, Shirahata A, Igarashi K. Correlation between the inhibition of cell growth by accumulated polyamines and the decrease of magnesium and ATP. Eur J Biochem 1993;217:89–96.10.1111/j.1432-1033.1993.tb18222.xSearch in Google Scholar PubMed

15. Averill-Bates DA, Ke Q, Tanel A, Roy J, Fortier G, Agostinelli E. Mechanism of cell death induced by spermine and amine oxidase in mouse melanoma cells. Int J Oncol 2008;32:79–88.10.3892/ijo.32.1.79Search in Google Scholar

16. Koenig H, Goldstone AD, Trout JJ, Lu CY. Polyamines mediate uncontrolled calcium entry and cell damage in rat heart in the calcium paradox. J Clin Invest 1987;80:1322–31.10.1172/JCI113209Search in Google Scholar PubMed PubMed Central

17. Thomas T, Gunnia UB, Yurkow EJ, Seibold JR, Thomas TJ. Inhibition of calcium signalling in murine splenocytes by polyamines: differential effects on CD4 and CD8 T-cells. Biochem J 1993;291:375–81.10.1042/bj2910375Search in Google Scholar PubMed PubMed Central


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/znc-2019-0119).


Received: 2019-06-23
Revised: 2020-01-06
Accepted: 2020-01-21
Published Online: 2020-02-24
Published in Print: 2020-03-26

©2020 Walter de Gruyter GmbH, Berlin/Boston

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