Impact of roscovitine, a selective CDK inhibitor, on cancer cells: bi-functionality increases its therapeutic potential

• Authors: Józefa Węsierska-Gądek , Andreea Borza , Oxana Komina , Margarita Maurer
• Languages of publication: EN

Abstracts

EN

Increased expression and activity of proteins driving cell cycle progression as well as inactivation of endogenous inhibitors of cyclin-dependent kinases (CDKs) enhance the proliferative potential of cells. Escape of cells during malignant transformation from the proper cell cycle control rendering them independent from growth factors provides rationale for therapeutic targeting of CDKs. Exposure of rapidly growing human MCF-7 breast cancer and HeLa cervix cancer cells to roscovitine (ROSC), a selective inhibitor of CDKs, inhibits their proliferation by induction of cell cycle arrest and/or apoptosis. The outcome strongly depends on the intrinsic traits of the tumor cells, on their cell cycle status prior to the onset of treatment and also on ROSC concentration. At lower dose ROSC primarily inhibits the cell cycle-related CDKs resulting in a strong cell cycle arrest. Interestingly, ROSC arrests asynchronously growing cells at the G2/M transition irrespective of the status of their restriction checkpoint. However, the exposure of cancer cells synchronized after serum starvation in the late G1 phase results in a transient G1 arrest only in cells displaying the intact G1/S checkpoint. At higher dosage ROSC triggers apoptosis. In HeLa cells inhibition of the activity of CDK7 and, in consequence, that of RNA polymerase II is a major event that facilitates the initiation of caspase-dependent apoptosis. In contrast, in the caspase-3-deficient MCF-7 breast cancer cells ROSC induces apoptosis by a p53-dependent pathway. HIPK2-mediated activation of the p53 transcription factor by phosphorylation at Ser46 results in upregulation of p53AIP1 protein. This protein after de novo synthesis and translocation into the mitochondria promotes depolarization of the mitochondrial membrane.

Keywords

EN

inhibitors of cyclin-dependent kinases; cell cycle arrest; cyclin-dependent kinases; apoptosis; roscovitine

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2009
• Volume: 56
• Issue: 3
• Pages: 495-501

Dates

published

2009

received

2009-06-01

revised

2009-07-15

accepted

2009-08-25

(unknown)

2009-08-31

Contributors

author

Józefa Węsierska-Gądek

• Cell Cycle Regulation Group, Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

author

Andreea Borza

• Cell Cycle Regulation Group, Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

author

Oxana Komina

• Cell Cycle Regulation Group, Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

author

Margarita Maurer

• Cell Cycle Regulation Group, Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

References

• Besson A, Dowdy SF, Roberts JM (2008) CDK inhibitors: cell cycle regulators and beyond. Dev Cell 14: 159-169.
• Fisher RP (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 118: 5171-5180.
• Fischer PM, Lane DP (2000) Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem 7: 1213-1245.
• Havlicek L, Hanus J, Vesely J, Leclerc S, Meijer L, Shaw G, Strnad M (1997) Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 40: 408-412.
• Helt AM, Galloway DA (2003) Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. Carcinogenesis 24: 159-169.
• Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30: 630-641.
• Malumbres M, Barbacid M (2007) Cell cycle kinases in cancer. Curr Opin Genet Dev 17: 60-65.
• Malumbres M, Pevarello P, Barbacid M, Bischoff JR (2008) CDK inhibitors in cancer therapy: what is next? Trends Pharmacol Sci 29: 16-21.
• Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y (2000) p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102: 849-862.
• Palancade B, Bensaude O (2003) Investigating RNA polymerase II carboxyl-terminal domain (CTD) phosphorylation. Eur J Biochem 270: 3859-3870.
• Schang LM, Coccaro E, Lacasse JJ (2005) Cdk inhibitory nucleoside analogs prevent transcription from viral genomes. Nucleosides Nucleotides Nucleic Acids 24: 829-837.
• Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129-1136.
• Vindelov LL, Christensen IJ, Nissen NI (1983) A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry 3: 323-327.
• Wesierska-Gadek J, Schmid G (2000) Overexpressed poly(ADP-ribose) polymerase delays the release of rat cells from p53-mediated G1 checkpoint. J Cell Biochem 80: 85-103.
• Wesierska-Gadek J, Schloffer D, Kotala V, Horky M (2002) Escape of p53 protein from E6-mediated degradation in HeLa cells after cisplatin therapy. Int J Cancer 101: 128-136.
• Wesierska-Gadek J, Gueorguieva M, Horky M (2005) Roscovitine-induced up-regulation of p53AIP1 protein precedes the onset of apoptosis in human MCF-7 breast cancer cells. Mol Cancer Ther 4: 113-124.
• Wesierska-Gadek J, Schmitz ML, Ranftler C (2007) Roscovitine-activated HIP2 kinase induces phosphorylation of wt p53 at Ser-46 in human MCF-7 breast cancer cells. J Cell Biochem 100: 865-874.
• Wesierska-Gadek J, Hajek SB, Sarg B, Wandl S, Walzi E, Lindner H (2008a) Pleiotropic effects of selective CDK inhibitors on human normal and cancer cells. Biochem Pharmacol 76: 1503-1514.
• Wesierska-Gadek J, Wandl S, Kramer M, Pickem C, Krystof V, Hajek SB (2008b) Roscovitine up-regulates p53 protein and induces apoptosis in human HeLaS3 cervix carcinoma cells. J. Cell Biochem 105: 1161-1171.
• Wojciechowski J, Horky M, Gueorguieva M, Wesierska-Gadek J (2003) Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine-induced apoptosis of human MCF-7 breast cancer cells. Int J Cancer 106: 486-495.