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Authors: Valentina Caracciolo, Giulio Laurenti, Gaetano Romano, Vincenzo Carnevale, Anna Maria Cimini, Catena Crozier-Fitzgerald, Emilio Gentile Warschauer, Giuseppe Russo and Antonio Giordano

Valentina Caracciolo

These authors contributed equally to this work.; Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA

Giulio Laurenti

These authors contributed equally to this work.; Department of Basic and Applied Biology; University of L’Aquila; Coppito, L’Aquila, Italy

Gaetano Romano

Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA

Vincenzo Carnevale

Institute for Computational Molecular Science; Department of Chemistry; College of Science and Technology; Temple University; Philadelphia, PA USA

Anna Maria Cimini

Department of Basic and Applied Biology; University of L’Aquila; Coppito, L’Aquila, Italy

Catena Crozier-Fitzgerald

Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA

Emilio Gentile Warschauer

Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA

Giuseppe Russo

Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA

Antonio Giordano

Corresponding author: antonio.giordano@temple.edu
Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA; Department of Human Pathology and Oncology; University of Siena; Siena, Italy

Abstract:
Cdk9 and Cdk7 are cdc2-like serine/threonine kinases that stabilize RNA transcript elongation through RNA polII carboxyl terminal domain (CTD) phosphorylation and are considered suitable targets for cancer therapy.

The effects of flavopiridol and of siRNA-mediated inhibition of Cdk9 and/or Cdk7 were analyzed in human glioblastoma and human prostate cancer cell lines.

One finding revealed that Cdk9 and Cdk7 could substitute each other in RNA polII CTD phosphorylation in contrast to the in vitro system. Thus, a simultaneous inhibition of Cdk9 and Cdk7 might be required both for targeting malignant cells and developing a platform for microarray analysis. However, these two pathways are not redundant, as indicated by differential effects observed in cell cycle regulation following siRNA-mediated inhibition of Cdk9 and/or Cdk7 in human PC3 prostate cancer cell line. Specifically, siRNA-mediated inhibition of Cdk9 caused a shift from G₀/G₁ to G₂/M phase in human PC3 prostate cancer cell line.

Another finding showed that flavopiridol treatment induced a substantial AKT-Ser473 phosphorylation in human glioblastoma T98G cell line in contrast to siRNA-mediated inhibition of Cdk9 and Cdk9 combined with Cdk7, whereas siRNA-mediated silencing of Cdk7 caused a minor increase in AKT-Ser473 phosphorylation. AKT-Ser473 is a hallmark of AKT pathway activation and may protect cells from apoptosis. This finding also shows that Cdk9 and Cdk7 pathways are not redundant and may have important implications in drug development and for studying the mechanism of chemoresistance in malignant cells.

Received: December 8, 2011; Accepted: February 8, 2012

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