Abstract
N,N-dimethyl-D-erythro-sphingosine (DMS), an N-methyl derivative of sphingosine, is an inhibitor of protein kinase C (PKC) and sphingosine kinase (SK). In previous reports, DMS-induced intracellular Ca2+ increase concentration ([Ca2+]i) was studied in T lymphocytes, monocytes, astrocytes and neuronal cells. In the present study, we studied DMS-induced increase of [Ca2+]i in HCT116 human colon cancer cells. We found that the DMS-induced increase of [Ca2+]i in colon cancer cells is composed of Ca2+ release from intracellular Ca2+ stores and subsequent Ca2+ influx. The Ca2+ release is not related to modulation of inositol 1,4,5-trisphosphate (IP3) receptor or ryanodine receptor. On the other hand, the Ca2+ influx is mediated largely through Ca2+ channels sensitive to verapamil, nifedipine, Ga3+, and La3+. Furthermore, we found that the response is inhibited by bepridil and Ni2+, specific inhibitors of Na+-Ca2+-exchanger, suggesting involvement of Na+-Ca2+ exchanger in the DMS-induced [Ca2+]i increase in colon cancer cells. This inhibition was also observed in U937 monocytes, but not in 1321N1 astrocytes.
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Abbreviations
- DMS:
-
N,N-Dimethyl-D-erythro-sphingosine
- NCX:
-
Na+-Ca2+-exchanger
- NSCC:
-
Non-specific cation channels
- [Ca2+ i :
-
Intracellular Ca2+ increase concentration
- IP3R:
-
Inositol 1,4,5-trisphosphates receptor
- RyR:
-
Ryanodine receptor
References
Abdel-Ghany, M., Osusky, M., Igarashi, Y., Hakomori, S., Shalloway, D., and Racker, R., Substrate-specific modulation of Src-mediated phosphorylation of Ras and caseins by sphingosines and other substrate modulators. Biochim. Biophys. Acta., 1137, 349–355 (1992).
Alfonso, A., De la Rosa, L. A., Vieytes, M. R., and Botana, L. M., Dimethylsphingosine increases cytosolic calcium and intracellular pH in human T lymphocytes. Biochem. Pharmacol., 65, 465–478 (2003).
Chang, Y. J., Lee, Y. K., Lee, E. H., Park, J. J., Chung, S. K., and Im, D. S., Structure-activity relationships of dimethylsphingosine (DMS) derivatives and their effects on intracellular pH and Ca2+ in the U937 monocyte cell line. Arch. Pharm. Res., 29, 657–665 (2006).
Groenendyk, J., Lynch, J., and Michalak, M., Calreticulin, Ca2+, and calcineurin — signaling from the endoplasmic reticulum. Mol. Cells, 17, 383–389 (2004).
Himmel, H. M., Meyer zu Heringdorf, D., Windorfer, B., van Koppen, C. J., Ravens, U., and Jakobs, K. H., Guanine nucleotide-sensitive inhibition of L-type Ca2+ current by lysosphingolipids in RINm5F insulinoma cells. Mol. Pharmacol., 53, 862–869 (1998).
Igarashi, Y. and Hakomori, S., Enzymatic synthesis of N,N-dimethyl-sphingosine: demonstration of the sphingosine: N-methyltransferase in mouse brain. Biochem. Biophys. Res. Commun., 164, 1411–1416 (1989).
Igarashi, Y., Kitamura, K., Toyokuni, T., Dean, B., Fenderson, B., Ogawass, T., and Hakomori, S., A specific enhancing effect of N,N-dimethylsphingosine on epidermal growth factor receptor autophosphorylation. Demonstration of its endogenous occurrence (and the virtual absence of unsubstituted sphingosine) in human epidermoid carcinoma A431 cells. J. Biol. Chem., 265, 5385–5389 (1990).
Kang, Y. K. and Park, M. K., Endoplasmic reticulum Ca2+ store: regulation of Ca2+ release and reuptake by intracellular and extracellular Ca2+ in pancreatic acinar cells. Mol. Cells, 19, 268–278 (2005).
Kobayashi, T., Mitsuo, K., and Goto, I., Free sphingoid bases in normal murine tissues. Eur. J. Biochem., 172, 747–752 (1988).
Lee, E. H., Lee, Y. K., Im, Y. J., Kim, J. H., Okajima, F., and Im, D. S., Dimethylsphingosine regulates intracellular pH and Ca(2+) in human monocytes. J. Pharmacol. Sci., 100, 289–296 (2006).
Lee, Y. K., Im, Y. J., Kim, Y. L., and Im, D. S., Characterization of Ca(2+) influx induced by dimethylphytosphingosine and lysophosphatidylcholine in U937 monocytes. Biochem. Biophys. Res. Commun., 348, 1116–1122 (2006).
Lee, Y. K., Kim, H. L., Kim, Y. L., and Im, D. S., Multiple actions of dimethylsphingosine in 1321N1 astrocytes. Mol. Cells, 23, 11–16 (2007).
Lee, Y. K., Lee, E. H., Chang, Y. J., Park, J. J., Chun, S. K., and Im, D. S., Structure-activity relationship of dimethylsphingosine on intracellular pH and Ca2+ in U937 monocytes. Arch. Pharm. Res., (2006).
Lipskaia, L. and Lompre, A. M., Alteration in temporal kinetics of Ca2+ signaling and control of growth and proliferation. Biol. Cell, 96, 55–68 (2004).
Mano, N., Oda, Y., Yamada, K., Asakawa, N., and Katayama, K., Simultaneous quantitative determination method for sphingolipid metabolites by liquid chromatography/ionspray ionization tandem mass spectrometry. Anal. Biochem., 244, 291–300 (1997).
Mathes, C., Fleig, A., and Penner, R., Calcium release-activated calcium current (ICRAC) is a direct target for sphingosine. J. Biol. Chem., 273, 25020–25030 (1998).
Megidish, T., Cooper, J., Zhang, L., Fu, H., and Hakomori, S., A novel sphingosine-dependent protein kinase (SDK1) specifically phosphorylates certain isoforms of 14-3-3 protein. J. Biol. Chem., 273, 21834–21845 (1998).
Meyer zu Heringdorf, D., Lass, H., Alemany, R., Laser, K. T., Neumann, E., Zhang, C., Schmidt, M., Rauen, U., Jakobs, K. H., and van Koppen, C. J., Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors. Embo. J., 17, 2830–2837 (1998).
Pushkareva, M., Khan, W. A., Alessenko, A. V., Sahyoun, N., and Hannun, Y. A., Sphingosine activation of protein kinases in Jurkat T cells. In vitro phosphorylation of endogenous protein substrates and specificity of action. J. Biol. Chem., 267, 15246–15251 (1992).
Sakakura, C., Sweeney, E. A., Shirahama, T., Hagiwara, A., Yamaguchi, T., Takahashi, T., Hakomori, S., and Igarashi, Y., Selectivity of sphingosine-induced apoptosis. Lack of activity of DL-erythyro-dihydrosphingosine. Biochem. Biophys. Res. Commun., 246, 827–830 (1998).
Shin, Y., Daly, J. W., and Choi, O. H., Diverse effects of sphingosine on calcium mobilization and influx in differentiated HL-60 cells. Cell Calcium, 27, 269–280 (2000).
Yun, M. R., Okajima, F., and Im, D. S., The action mode of lysophosphatidylcholine in human monocytes. J. Pharmacol. Sci., 94, 45–50 (2004).
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Kim, HL., Im, DS. N,N-dimethyl-D-erythro-sphingosine increases intracellular Ca2+ concentration via Na+-Ca2+-exchanger in HCT116 human colon cancer cells. Arch. Pharm. Res. 31, 54–59 (2008). https://doi.org/10.1007/s12272-008-1120-y
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DOI: https://doi.org/10.1007/s12272-008-1120-y