Abstract
In recent years, increasing evidence indicated the importance of a deregulated c-myc gene in the melanoma pathogenesis. We have previously demonstrated that treatment of melanoma cells with c-myc antisense oligodeoxynucleotides can inhibit cell proliferation and activate apoptosis. To gain insight into the mechanisms activated by Myc down-regulation, we have now developed an experimental model that allows modulating Myc protein expression in melanoma cells. This was achieved by originating stable melanoma cell clones expressing ecdysone-inducible c-myc antisense RNA. We show that the induction of c-myc antisense RNA in M14 melanoma cells leads to an inhibition of cell proliferation characterized by accumulation of cells in the G1 phase of the cell cycle (up to 80%) and activation of apoptosis (50%). These data are associated with an increase of p27kip1 levels and a significant reduction of the cdk2-associated kinase activity. In addition, we show that an ectopic overexpression of p27kip1 in this experimental model can enhance the apoptotic rate. Our results indicate that down-regulation of Myc protein induces a G1 arrest and activates apoptosis by increasing p27kip1 content in melanoma cells, that are known to be defective for the p16-cyclinD/cdk4-pRb G1 checkpoint. This is particularly relevant for identifying new therapeutic strategies based on the re-establishment of the apoptotic pathways in cancer cells.
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Acknowledgements
We thank Maurizia Caruso for critically reading the manuscript; and Alessandra Rinaldi for technical assistance. This work was supported by grants from CNR, Target Project on Biotechnology (to I D'Agnano) and Progetto Strategico ‘Oncologia’ MURST-CNR (to A Felsani).
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D'Agnano, I., Valentini, A., Fornari, C. et al. Myc down-regulation induces apoptosis in M14 melanoma cells by increasing p27kip1 levels. Oncogene 20, 2814–2825 (2001). https://doi.org/10.1038/sj.onc.1204392
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DOI: https://doi.org/10.1038/sj.onc.1204392
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