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RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

Oncogene volume 27, pages 5315–5325 (2008)Cite this article

Abstract

The MAPK MEK/ERK pathway is often upregulated in cancer cells and represents an attractive target for development of anticancer drugs. Only few data concerning the specific functions of ERK1 and 2 are reported in the literature. In this report, we investigated the specific role of ERK1 and 2 in liver tumor growth both in vitro and in vivo. DNA synthesis and cells in S phase analysed by flow cytometry, correlated with strong inhibition of Cdk1 and cyclin E levels, are strongly reduced after exposure to the MEK inhibitor, U0126. We obtained a significant reduction of colony formation in soft agar assays and a reduction in the size of tumor xenografts in nude mice treated with U0126. Then, we could specifically abolished ERK1 or 2 expression by small-interfering RNA (siRNA) and demonstrated that ERK2 knockdown but not ERK1 interferes with the process of replication. Moreover, we found that colony formation and tumor growth in vivo were significantly inhibited by targeting ERK2 using stable chemically modified siRNA. Taken together, our results emphasize the importance of the MEK/ERK pathway in liver cancer cell growth in vitro and in vivo and argue for a crucial role of ERK2 in this regulation.

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Abbreviations

cdk:

cyclin-dependent kinase

ERK:

extracellular signal-regulated kinase

HCC:

hepatocellular carcinoma

LNA:

locked nucleic acid

MEK:

mitogen-activated protein kinase

siRNA:

small-interfering RNA

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Acknowledgements

We thank Dr P Loyer for flow cytometry advices, Sigma-Aldrich and Dr Heike Lehrmann for giving us the LNA ERK2 oligonucleotides, and C Ribault for technical assistance. This research was supported by the Institut National de la Santé et de la Recherche Médicale and the Association pour la Recherche sur le Cancer (ARC). A Bessard and C Frémin are a recipient of fellowship from the Région Bretagne/INSERM and the Ministère de l′Education Nationale et de la Technologie, respectively, and the ARC.

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Authors and Affiliations

  1. INSERM U522, IFR 140, Hopital Pontchaillou, Université de Rennes1, Rennes, France

    A Bessard, C Frémin, F Ezan, L Gailhouste & G Baffet

  2. Plate-forme d'Histo-Pathologie, IFR140, Université de Rennes 1 CHU de Rennes, France

    A Fautrel

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  1. A Bessard
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Correspondence to G Baffet.

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Bessard, A., Frémin, C., Ezan, F. et al. RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo. Oncogene 27, 5315–5325 (2008). https://doi.org/10.1038/onc.2008.163

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