Cell Growth & Differentiation, Vol 8, Issue 3 327-334, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Effects of rottlerin, an inhibitor of calmodulin-dependent protein kinase III, on cellular proliferation, viability, and cell cycle distribution in malignant glioma cells

TG Parmer, MD Ward and WN Hait
Department of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway 08854-5638, USA.

Calmodulin-dependent protein kinases phosphorylate certain substrates that have been implicated in regulating cellular proliferation. For example, upon mitogenic stimulation, there is a rapid activation of calmodulin-dependent protein kinase III (CaM kinase III), which leads to the phosphorylation of elongation factor 2. Recently, our laboratory demonstrated that the activity of CaM kinase III is increased in glioma cells following exposure to mitogens and is diminished or absent in nonproliferating glial tissue. Rottlerin, a 5,7-dihydroxy-2,2-dimethyl-6-(2,4,6-trihydroxy-3-methyl-5-acetylbenzy l)-8-cinnamoyl-1,2-chromene isolated from the pericarps of Mallotus phillippinensis, has been shown to be an effective CaM kinase III inhibitor. Therefore, we evaluated the effects of rottlerin on the growth and viability of glioblastoma cell lines. Rottlerin decreased growth and induced cytotoxicity in rat (C6) and two human gliomas (T98G and U138MG) at concentrations that inhibited the activity of CaM kinase III in vitro and in vivo. Far less demonstrable effects were observed on other Ca2++/CaM-sensitive kinases. Incubation of glial cells with rottlerin produced a block at the G1-S interface and the appearance of a population of cells with a <2N complement of DNA. In addition, rottlerin induced changes in cellular morphology such as cell shrinkage, accumulation of cytoplasmic vacuoles, and packaging of cellular components within membranes. These data suggest that CaM kinase III may be an important link between the activation of CaM-dependent signaling, proliferation, and viability in malignant cells, and that inhibition of CaM kinase III may represent an interesting pharmacological target in malignant gliomas.

This article has been cited by other articles:

				N. Sud, S. Wedgwood, and S. M. Black Protein kinase C{delta} regulates endothelial nitric oxide synthase expression via Akt activation and nitric oxide generation Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L582 - L591. [Abstract] [Full Text] [PDF]

				L. Q. Hong-Brown, C. R. Brown, D. S. Huber, and C. H. Lang Alcohol Regulates Eukaryotic Elongation Factor 2 Phosphorylation via an AMP-activated Protein Kinase-dependent Mechanism in C2C12 Skeletal Myocytes J. Biol. Chem., February 9, 2007; 282(6): 3702 - 3712. [Abstract] [Full Text] [PDF]

				B.-H. Choi, E.-M. Hur, J.-H. Lee, D.-J. Jun, and K.-T. Kim Protein kinase C{delta}-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death J. Cell Sci., April 1, 2006; 119(7): 1329 - 1340. [Abstract] [Full Text] [PDF]

				H. Wu, J.-M. Yang, S. Jin, H. Zhang, and W. N. Hait Elongation factor-2 kinase regulates autophagy in human glioblastoma cells. Cancer Res., March 15, 2006; 66(6): 3015 - 3023. [Abstract] [Full Text] [PDF]

				S. Arora, J.-M. Yang, and W. N. Hait Identification of the Ubiquitin-Proteasome Pathway in the Regulation of the Stability of Eukaryotic Elongation Factor-2 Kinase Cancer Res., May 1, 2005; 65(9): 3806 - 3810. [Abstract] [Full Text] [PDF]

				T. B. Deb, C. M. Coticchia, and R. B. Dickson Calmodulin-mediated Activation of Akt Regulates Survival of c-Myc-overexpressing Mouse Mammary Carcinoma Cells J. Biol. Chem., September 10, 2004; 279(37): 38903 - 38911. [Abstract] [Full Text] [PDF]

				S. Arora, J.-M. Yang, R. Utsumi, T. Okamoto, T. Kitayama, and W. N. Hait P-Glycoprotein Mediates Resistance to Histidine Kinase Inhibitors Mol. Pharmacol., September 1, 2004; 66(3): 460 - 467. [Abstract] [Full Text] [PDF]

				S. Arora, J.-M. Yang, T. G. Kinzy, R. Utsumi, T. Okamoto, T. Kitayama, P. A. Ortiz, and W. N. Hait Identification and Characterization of an Inhibitor of Eukaryotic Elongation Factor 2 Kinase against Human Cancer Cell Lines Cancer Res., October 15, 2003; 63(20): 6894 - 6899. [Abstract] [Full Text] [PDF]

				J. Yang, J.-M. Yang, M. Iannone, W. J. Shih, Y. Lin, and W. N. Hait Disruption of the EF-2 Kinase/Hsp90 Protein Complex: A Possible Mechanism to Inhibit Glioblastoma by Geldanamycin Cancer Res., May 1, 2001; 61(10): 4010 - 4016. [Abstract] [Full Text]

				J. Pongracz, P. Webb, K. Wang, E. Deacon, O. J. Lunn, and J. M. Lord Spontaneous Neutrophil Apoptosis Involves Caspase 3-mediated Activation of Protein Kinase C-delta J. Biol. Chem., December 24, 1999; 274(52): 37329 - 37334. [Abstract] [Full Text] [PDF]