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p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

Oncogene volume 23, pages 3726–3731 (2004)Cite this article

Abstract

Chondrosarcomas represent the second most frequent class of primary skeletal malignancies. This tumor type is highly resistant to radiation therapy and currently available chemotherapies, thereby limiting treatment choice to surgical resection. Identifying the mechanisms responsible for chondrosarcoma cell proliferation is therefore crucial for the development of new treatment strategies. Here, we demonstrate a significant reduction in rat chondrosarcoma cell proliferation following treatment with pharmacological inhibitors (SB202190 and PD169316) of p38 mitogen-activated protein (MAP) kinases. In an attempt to dissect possible mechanisms, we investigated the effect of p38 inhibition on promoter activity of cell-cycle genes. Surprisingly, p38 inhibition resulted in upregulation of the activities of all three D-type cyclin promoters. In addition, p38 inhibitors induced increased transcription of the cell-cycle inhibitor p21waf1/cip1. As expected, promoter activity of the cyclin A gene, which lies downstream of D-type cyclins and p21 in cell-cycle progression, was strongly reduced by p38 inhibitors. These effects were independent of a cyclic AMP response element and conferred by the proximal 150 nucleotides of the cyclin A promoter. Decreased transcription was accompanied by greatly reduced cyclin A protein levels upon p38 inhibition. These observations indicate complex regulation of chondrosarcoma cell-cycle progression by p38 signaling, and suggest that components of p38 MAP kinase pathways may be effective targets in the treatment of these tumors.

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Acknowledgements

We are grateful to Drs K Oda, D Shiffman, RG Pestell, and B Vogelstein for the generous gift of plasmids. This work was supported by funds from the Canadian Institutes of Health Research, the Canadian Arthritis Network, and the Department of Physiology, University of Western Ontario to FB.

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  1. Dalia Halawani

    Present address: Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, Quebec, Canada, H3G 1A6

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Canadian Institute of Health Research Group in Skeletal Development and Remodeling, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Dalia Halawani, Rhoda Mondeh, Lee-Anne Stanton & Frank Beier

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  1. Dalia Halawani
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Correspondence to Frank Beier.

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Halawani, D., Mondeh, R., Stanton, LA. et al. p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation. Oncogene 23, 3726–3731 (2004). https://doi.org/10.1038/sj.onc.1207422

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