Advertisement

Biological Trace Element Research

, Volume 150, Issue 1–3, pp 477–486 | Cite as

Biphasic Dose-Dependent Effect of Lithium Chloride on Survival of Human Hormone-Dependent Breast Cancer Cells (MCF-7)

  • Muralidharan Suganthi
  • Gopalakrishnan Sangeetha
  • Govindaraj Gayathri
  • Bhaskaran Ravi Sankar
Article

Abstract

Lithium, the first element of Group I in the periodic system, is used to treat bipolar psychiatric disorders. Lithium chloride (LiCl) is a selective inhibitor of glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase that regulates many cellular processes, in addition to its role in the regulation of glycogen synthase. GSK-3β is emerged as a promising drug target for various neurological diseases, type-2 diabetes, cancer, and inflammation. Several works have demonstrated that lithium can either inhibit or stimulate growth of normal and cancer cells. Hence, the present study is focused to analyze the underlying mechanisms that dictate the biphasic oncogenic properties of LiCl. In the current study, we have investigated the dose-dependent effects of LiCl on human breast cancer cells (MCF-7) by assessing the consequences on cytotoxicity and protein expressions of signaling molecules crucial for the maintenance of cell survival. The results showed breast cancer cells respond in a diverse manner to LiCl, i.e., at lower concentrations (1, 5, and 10 mM), LiCl induces cell survival by inhibiting apoptosis through regulation of GSK-3β, caspase-2, Bax, and cleaved caspase-7 and by activating anti-apoptotic proteins (Akt, β-catenin, Bcl-2, and cyclin D1). In contrast, at high concentrations (50 and 100 mM), it induces apoptosis by reversing these effects. Moreover, LiCl also alters the sodium and potassium levels thereby altering the membrane potential of MCF-7 cells. Thus it is inferred that LiCl exerts a dose-dependent biphasic effect on breast cancer cells (MCF-7) by altering the apoptotic/anti-apoptotic balance.

Keywords

Breast cancer Lithium chloride GSK-3β β-catenin 

Abbreviations

ANOVA

Analysis of variance

Bax

Bcl2-associated X protein 1

Bcl-2

B cell lymphoma 2

CM

Conditioned medium

DMEM

Dulbecco's modified Eagle's medium

ECF

Extracellular fluid

EDTA

Ethylenediaminetetraacetic acid

FBS

Fetal bovine serum

GSK-3β

Glycogen synthase kinase-3β

LiCl

Lithium chloride

Notes

Acknowledgments

One of the authors (M. Suganthi) acknowledge on of the authors the financial support for this study from UGC-Research Fellowships in Sciences for Meritorious Students (UGC-RFSMS) programme. This study is financially supported by UGC-Special Assistance Programme (UGC-SAP), New Delhi, India.

References

  1. 1.
    Weiner ML (1991) Overview of lithium toxicology. In: Schrauzer GN, Klippel KF (eds) Lithium in biology and medicine. Weinheim, VCH, pp 83–99Google Scholar
  2. 2.
    Dawson EB (1991) The relationship of tap water and physiological levels of lithium to mental hospital admission and homicide in Texas. In: Schrauzer GN, Klippel KF (eds) Lithium in biology and medicine. Weinheim, VCH, pp 171–187Google Scholar
  3. 3.
    Okusa MD, Crystal LJ (1994) Clinical manifestations and management of acute lithium intoxication. Am J Med 97:383–389PubMedCrossRefGoogle Scholar
  4. 4.
    Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J (1997) Lithium. In: Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J (eds) Medical toxicology: diagnosis and treatment of human poisoning. Williams and Wilkins, Baltimore, p 1579Google Scholar
  5. 5.
    Henry GC (1998) Lithium. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RS (eds) Toxicologic emergencies. Appleton and Lange, Stamford, p 969Google Scholar
  6. 6.
    Ward ME, Musa MN, Bailey L (1994) Clinical pharmacokinetics of lithium. J Clin Pharmacol 34:280–285PubMedGoogle Scholar
  7. 7.
    Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci 93:8455–8459. doi: 10.1073/pnas.93.16.8455 PubMedCrossRefGoogle Scholar
  8. 8.
    Ryves WJ, Harwood AJ (2001) Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 280:720–725PubMedCrossRefGoogle Scholar
  9. 9.
    Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95–102PubMedCrossRefGoogle Scholar
  10. 10.
    Welshons WV, Engler KS, Taylor JA, Grady LH, Curran EM (1995) Lithium-stimulated proliferation and alteration of phosphoinositide metabolites in MCF-7 human breast cancer cells. J Cell Physiol 165:134–144PubMedCrossRefGoogle Scholar
  11. 11.
    Kang HJ, Noh JS, Bae YS, Gwag BJ (2003) Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase C gamma. Mol Pharmacol 64:228–234PubMedCrossRefGoogle Scholar
  12. 12.
    Chuang DM (2005) The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci 1053:195–204PubMedCrossRefGoogle Scholar
  13. 13.
    Rao AS, Kremenevskaja N, Resch J, Brabant G (2005) Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling. Eur J Endocrinol 153:929–938PubMedCrossRefGoogle Scholar
  14. 14.
    Chen CL, Lin CF, Chiang CW, Jan MS, Lin YS (2006) Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis. Mol Pharmacol 70:510–517PubMedCrossRefGoogle Scholar
  15. 15.
    Sinha D, Wang Z, Ruchalski KL, Levine JS, Krishnan S, Lieberthal W, Schwartz JH, Borkan SC (2005) Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors. Am J Physiol Renal 288:F703–F713CrossRefGoogle Scholar
  16. 16.
    Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi H, Konishi Y, Mohseni M, Wang G, Rosen DM, Denmeade SR, Higgins MJ, Vitolo MI, Bachman KE, Park BH (2009) Knocking of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci 106:2835–2840PubMedCrossRefGoogle Scholar
  17. 17.
    Erdal E, Ozturk N, Cagatay T, Eksioglu-Demiralp E, Ozturk M (2005) Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells. Int J Cancer 115:903–910PubMedCrossRefGoogle Scholar
  18. 18.
    Song L, Zhou T, Jope RS (2004) Lithium facilitates apoptotic signaling induced by activation of the Fas death domain-containing receptor. BMC Neurosci 5:20PubMedCrossRefGoogle Scholar
  19. 19.
    Tang HR, He Q (2003) Effects of lithium chloride on the proliferation and apoptosis of K562 leukemia cells. Hunan Yi Ke Da Xue Xue Bao 28:357–360PubMedGoogle Scholar
  20. 20.
    Tseng WP, Lin-Shiau SY (2002) Long-term lithium treatment prevents neurotoxic effects of beta-bungarotoxin in primary cultured neurons. J Neurosci Res 69:633–641PubMedCrossRefGoogle Scholar
  21. 21.
    Gelfand EW, Dosch NH, Hastings D, Shore A (1979) Lithium: a modulator of cyclic AMP-dependent levels in lymphocytes. Science 203:365–367PubMedCrossRefGoogle Scholar
  22. 22.
    Hart DA (1979) Potentiation of phytohemagglutinin stimulation of lymphoid cells by lithium. Exp Cell Res 121:419–425PubMedCrossRefGoogle Scholar
  23. 23.
    Avissar S, Schreiber G, Danon A, Belmaker RH (1988) Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature 331:440–442PubMedCrossRefGoogle Scholar
  24. 24.
    Drummond AH (1988) Lithium affects G-protein receptor coupling. Nature 331:388PubMedCrossRefGoogle Scholar
  25. 25.
    Ziaie Z, Kefalides NA (1989) Lithium chloride restores host protein synthesis in herpes simplex virus-infected endothelial cells. Biochem Biophys Res Commun 160:1073–1078PubMedCrossRefGoogle Scholar
  26. 26.
    Madiehe AM, Mampuru LJ, Tyobeka EM (1995) Induction of apoptosis in HL-60 cells by lithium. Biochem Biophys Res Commun 209:768–774PubMedCrossRefGoogle Scholar
  27. 27.
    Inaba K, Utsugi J, Kuroda T, Tsuda M, Tsuchiya T (1997) Na+(Li+)/H+ antiporter in Pseudomonas aeruginosa and effect of Li+ on cell growth. Biol Pharm Bull 20:621–624PubMedCrossRefGoogle Scholar
  28. 28.
    Oliveira AG, Soares MJ, Pinto AS (1997) Ultrastructural alterations induced by lithium chloride in DNA-containing organelles of a bat trypanosome. Mem Inst Oswaldo Cruz 92:513–516PubMedCrossRefGoogle Scholar
  29. 29.
    Tomooka Y, Imagawa W, Nandi S, Bern HA (1983) Growth effect of lithium on mouse mammary epithelial cells in serum-free collagen gel culture. J Cell Physiol 117:290–296PubMedCrossRefGoogle Scholar
  30. 30.
    Nakamura CV, Pinto AS (1989) Biological effects of lithium chloride on the insect trypanosomatid Herpetomonas samuelpessoai. Parasitology 2:193–197CrossRefGoogle Scholar
  31. 31.
    Hori C, Oka T (1979) Induction by lithium ion of multiplication of mouse mammary epithelium in culture. Proc Natl Acad Sci 76:2823–2827PubMedCrossRefGoogle Scholar
  32. 32.
    Ptashne K, Stockdale FE, Conlon S (1980) Initiation of DNA synthesis in mammary epithelium and mammary tumors by lithium ions. J Cell Physiol 103:41–46PubMedCrossRefGoogle Scholar
  33. 33.
    Rybak SM, Stockdale FE (1981) Growth effects of lithium chloride in BALB/c 3T3 fibroblasts and Madin–Darby canine kidney epithelial cells. Exp Cell Res 136:263–270PubMedCrossRefGoogle Scholar
  34. 34.
    Polotsky AJ, Zhu L, Santoro N, Pollard JW (2009) Lithium chloride treatment induces epithelial cell proliferation in xenografted human endometrium. Hum Reprod 24:1960–1967PubMedCrossRefGoogle Scholar
  35. 35.
    Ballin A, Aladjem M, Banyash M, Boichis H, Barzilay Z, Gal R, Witz IP (1983) The effect of lithium chloride on tumour appearance and survival of melanoma-bearing mice. Br J Cancer 48:83–87PubMedCrossRefGoogle Scholar
  36. 36.
    Sun A, Shanmugam I, Song J, Terranova PF, Thrasher JB, Li B (2007) Lithium suppresses cell proliferation by interrupting E2F-DNA interaction and subsequently reducing S-phase gene expression in prostate cancer. Prostate 9:976–988CrossRefGoogle Scholar
  37. 37.
    Zaragosi LE, Wdziekonski B, Fontaine C, Villageois P, Peraldi P, Dani C (2008) Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes. BMC Cell Biol 9:11PubMedCrossRefGoogle Scholar
  38. 38.
    Stump RJ, Lovicu FJ, Ang SL, Pandey SK, McAvoy JW (2006) Lithium stabilizes the polarized lens epithelial phenotype and inhibits proliferation, migration, and epithelial mesenchymal transition. J Pathol 210:249–257PubMedCrossRefGoogle Scholar
  39. 39.
    Laurenz JC, Smith SB (1998) Lithium chloride does not inhibit the proliferation of L6 myoblasts by decreasing intracellular free inositol. J Anim Sci 76:66–73PubMedGoogle Scholar
  40. 40.
    Suganthi M, Sangeetha G, Benson CS, Dinesh Babu S, Sathyavathy A, Sivakumar R, Ravi Sankar B (2012) In vitro mechanisms involved in the regulation of cell survival by lithium chloride and IGF-1 in human hormone-dependent breast cancer cells (MCF-7). Toxicol Lett 214:182–191Google Scholar
  41. 41.
    Sahebgharani M, Nejati M, Sepehrizadeh Z, Khorramizadeh MR, Bahrololoumi-Shapourabadi M, Hashemi-Bozchlou S, Esmaeili J, Ghazi-Khansari M (2008) Lithium chloride protects PC12 pheochromocytoma cell line from morphine-induced apoptosis. Arch Iran Med 11:639–648PubMedGoogle Scholar
  42. 42.
    Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6:1664–1668PubMedCrossRefGoogle Scholar
  43. 43.
    Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186PubMedCrossRefGoogle Scholar
  44. 44.
    Cohen P, Frame S (2001) The renaissance of GSK3. Nat Rev Mol Cell Biol 2:769–776PubMedCrossRefGoogle Scholar
  45. 45.
    Silva AK, Yi H, Hayes SH, Seigel GM, Hackam AS (2010) Lithium chloride regulates the proliferation of stem-like cells in retinoblastoma cell lines: a potential role for the canonical Wnt signaling pathway. Mol Vis 16:36–45PubMedGoogle Scholar
  46. 46.
    Tell S, Yi H, Jockovich ME, Murray TG, Hackam AS (2006) The Wnt signaling pathway has tumor suppressor properties in retinoblastoma. Biochem Biophys Res Commun 349:261–269PubMedCrossRefGoogle Scholar
  47. 47.
    Prange W, Breuhahn K, Fischer F, Zilkens C, Pietsch T, Petmecky K, Eilers R, Dienes HP, Schirmacher P (2003) Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. J Pathol 201:250–259PubMedCrossRefGoogle Scholar
  48. 48.
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790PubMedCrossRefGoogle Scholar
  49. 49.
    van Es JH, Giles RH, Clevers HC (2001) The many faces of the tumor suppressor gene APC. Exp Cell Res 264:126–134PubMedCrossRefGoogle Scholar
  50. 50.
    Roh MS, Hong SH, Jeong JS (2004) Gene expression profiling of breast cancers with emphasis of β-catenin regulation. J Korean Med Sci 19:275–282PubMedCrossRefGoogle Scholar
  51. 51.
    Lin SY, Xia W, Wang JC (2000) β-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci 97:4262–4266PubMedCrossRefGoogle Scholar
  52. 52.
    Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426PubMedCrossRefGoogle Scholar
  53. 53.
    Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ (2000) WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev 14:585–595PubMedGoogle Scholar
  54. 54.
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512PubMedCrossRefGoogle Scholar
  55. 55.
    Bartkova J, Lukas J, Müller H, Lüzhoft D, Strauss M, Bartek J (1994) Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353–361PubMedCrossRefGoogle Scholar
  56. 56.
    Weinstat-Saslow D, Merino MJ, Manrow RE, Lawrence JA, Bluth RF, Wittenbel KD, Simpson JF, Page DL, Steeg PS (1995) Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med 1:1257–1260PubMedCrossRefGoogle Scholar
  57. 57.
    Courjal F, Louason G, Speiser P, Katsaros D, Zeillinger R, Theillet C (1996) Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer 69:247–253PubMedCrossRefGoogle Scholar
  58. 58.
    Michalides R, Hageman P, van Tinteren H, Houben L, Wientjens E, Klompmaker R, Peterse J (1996) A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br J Cancer 73:728–734PubMedCrossRefGoogle Scholar
  59. 59.
    Hinds PW, Dowdy SF, Eaton EN, Arnold A, Weinberg RA (1994) Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci 91:709–713PubMedCrossRefGoogle Scholar
  60. 60.
    Lovec H, Sewing A, Lucibello FC, Müller R, Möröy T (1994) Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation. Oncogene 9:323–326PubMedGoogle Scholar
  61. 61.
    Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV (1994) Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669–671PubMedCrossRefGoogle Scholar
  62. 62.
    Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998) Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12:3499–3511PubMedCrossRefGoogle Scholar
  63. 63.
    Takahashi-Yanaga F, Sasaguri T (2008) GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy. Cell Signal 20:581–589PubMedCrossRefGoogle Scholar
  64. 64.
    Schotte P, Van Loo G, Carpentier I, Vandenabeele P, Beyaert R (2001) Lithium sensitizes tumor cells in an NF-kappa B-independent way to caspase activation and apoptosis induced by tumor necrosis factor (TNF). Evidence for a role of the TNF receptor-associated death domain protein. J Biol Chem 276:25939–25945PubMedCrossRefGoogle Scholar
  65. 65.
    Liao X, Zhang L, Thrasher JB, Du J, Li B (2003) Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer. Mol Cancer Ther 2:1215–1222PubMedGoogle Scholar
  66. 66.
    Yin XM (2000) Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways. Cell Res 10:161–167PubMedCrossRefGoogle Scholar
  67. 67.
    Mohamad N, Gutierrez A, Nunez M et al (2005) Mitochondrial apoptotic pathways. Biocell 29:149–161PubMedGoogle Scholar
  68. 68.
    Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183PubMedCrossRefGoogle Scholar
  69. 69.
    Chen RW, Chuang DM (1999) Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 274:6039–6042PubMedCrossRefGoogle Scholar
  70. 70.
    Bauer JH, Helfand SL (2006) The humble fly: what a model system can reveal about the human biology of aging. Med Health R I 89:314–315PubMedGoogle Scholar
  71. 71.
    Hartley CE, Buchan A, Randall S, Skinner GR, Osborne M, Tomkins LM (1993) The effects of lithium and potassium on macromolecular synthesis in herpes simplex virus-infected cells. J Gen Virol 74:1519–1525PubMedCrossRefGoogle Scholar
  72. 72.
    Coppen A, Shaw DM (1967) The distribution of electrolytes and water in patients after taking lithium carbonate. Lancet 2:805–806PubMedCrossRefGoogle Scholar
  73. 73.
    Gow IF, Ellis D (1990) Effect of lithium on the intracellular potassium concentration in sheep heart Purkinje fibres. Exp Physiol 75:427–430PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Muralidharan Suganthi
    • 1
  • Gopalakrishnan Sangeetha
    • 1
  • Govindaraj Gayathri
    • 1
  • Bhaskaran Ravi Sankar
    • 1
  1. 1.Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical SciencesUniversity of MadrasChennaiIndia

Personalised recommendations