Abstract
Staurosporine was found to bring about complete growth inhibition of human glioma cell lines. U87 MG cells were arrested in S phase while U373 MG cells in G2/M phase on staurosporine treatment. Consistent with this observation, no change in G1 phase regulators viz., Cyclin D1, D3 and CDK4 was seen on staurosporine treatment. The levels of CDK2, CDC2, Cyclin A and Cyclin B proteins decreased, while the levels of CDK inhibitors viz., p21 and p27 were found to increase on staurosporine treatment. The mRNA levels of CDK2 and CDC2 genes were also found to decrease on staurosporine treatment. Thus apart from staurosporine’s known direct inhibitory effect on CDK2 and CDC2 activities, staurosporine was found to down-regulate activities of these two kinases by modulating the expression of the kinases themselves as well that of their activating partners (Cyclins) and their inhibitors.
Similar content being viewed by others
References
Abe K, Yoshida M, Usui T, Horinouchi S, Beppu T (1991) Highly synchronous culture of fibroblasts from G2 block caused by staurosporine, a potent inhibitor of protein kinases. Exp Cell Res 192:122–127
Baltuch GH, Couldwell WT, Villemure JG, Yong VW (1993) Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines. A comparison between staurosporine and tamoxifen. Neurosurgery 33:495–501; discussion 501
Bredel M, Pollack IF (1997) The role of protein kinase C (PKC) in the evolution and proliferation of malignant gliomas, and the application of PKC inhibition as a novel approach to anti-glioma therapy. Acta Neurochir (Wien), 139:1000–1013
Bruno S, Ardelt B, Skierski JS, Traganos F, Darzynkiewicz Z (1992) Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes. Cancer Res 52:470–473
Couldwell WT, Antel JP, Yong VW (1992) Protein kinase C activity correlates with the growth rate of malignant gliomas: Part II. Effects of glioma mitogens and modulators of protein kinase C. Neurosurgery 31:717–724; discussion 724
Crissman HA, Gadbois DM, Tobey RA, Bradbury EM (1991) Transformed mammalian cells are deficient in kinase-mediated control of progression through the G1 phase of the cell cycle. Proc Natl Acad Sci USA 88:7580–7584
Gadbois DM, Hamaguchi JR, Swank RA, Bradbury EM (1992) Staurosporine is a potent inhibitor of p34cdc2 and p34cdc2-like kinases. Biochem Biophys Res Commun 184:80–85
Ikemoto H, Tani E, Matsumoto T, Nakano A, Furuyama J (1995) Apoptosis of human glioma cells in response to calphostin C, a specific protein kinase C inhibitor. J Neurosurg 83:1008–1016
Kim EH, Kim HS, Kim SU, Noh EJ, Lee JS, Choi KS (2005) Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene 24:6877–6889
Kim EH, Kim SU, Shin DY, Choi KS (2004) Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Oncogene 23:446–456
Kronfeld I, Zsukerman A, Kazimirsky G, Brodie C (1995) Staurosporine induces astrocytic phenotypes and differential expression of specific PKC isoforms in C6 glial cells. J Neurochem 65:1505–1514
Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC (1998) Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396:580–584
Lin Y, Chrest FJ, Gabrielson EW (1992) Reversible G1 arrest of a human lung epithelial cell line by staurosporine. J Cell Physiol 152:646–653
Meggio F, Donella Deana A, Ruzzene M, Brunati AM, Cesaro L, Guerra B, Meyer T, Mett H, Fabbro D, Furet P et al (1995) Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. Eur J Biochem 234:317–322
O’Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC, Altieri DC (2000) Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA 97:13103–13107
O’Driscoll KR, Teng KK, Fabbro D, Greene LA, Weinstein IB (1995) Selective translocation of protein kinase C-delta in PC12 cells during nerve growth factor-induced neuritogenesis. Mol Biol Cell 6:449–458
Okhrimenko H, Lu W, Xiang C, Hamburger N, Kazimirsky G, Brodie C (2005) Protein kinase C-epsilon regulates the apoptosis and survival of glioma cells. Cancer Res 65:7301–7309
Schnier JB, Gadbois DM, Nishi K, Bradbury EM (1994) The kinase inhibitor staurosporine induces G1 arrest at two points: effect on retinoblastoma protein phosphorylation and cyclin-dependent kinase 2 in normal and transformed cells. Cancer Res 54:5959–5963
Sharif TR, Sharif M (1999) Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples. Int J Oncol 15:237–243
Tamaoki T, Nomoto H, Takahashi I, Kato Y, Morimoto M, Tomita F (1986) Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase. Biochem Biophys Res Commun 135:397–402
Yamasaki F, Hama S, Yoshioka H, Kajiwara Y, Yahara K, Sugiyama K, Heike Y, Arita K, Kurisu K (2003) Staurosporine-induced apoptosis is independent of p16 and p21 and achieved via arrest at G2/M and at G1 in U251MG human glioma cell line. Cancer Chemother Pharmacol 51:271–283
Yong VW, Dooley NP, Noble PG (1994) Protein kinase C in cultured adult human oligodendrocytes: a potential role for isoform alpha as a mediator of process outgrowth. J Neurosci Res 39:83–96
Acknowledgements
This work was supported by grants from the Lady Tata Memorial Trust and Indian Council of Medical Research (N.V.S.) and a fellowship from the Council of Scientific and Industrial Research (M.N.H.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Harmalkar, M.N., Shirsat, N.V. Staurosporine-induced Growth Inhibition of Glioma Cells is Accompanied by Altered Expression of Cyclins, CDKs and CDK Inhibitors. Neurochem Res 31, 685–692 (2006). https://doi.org/10.1007/s11064-006-9068-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-006-9068-0