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JunD is involved in the antiproliferative effect of Δ9-tetrahydrocannabinol on human breast cancer cells

Abstract

It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells. Here we studied the mechanism of Δ9-tetrahydrocannabinol (THC) antiproliferative action in these cells, and show that it involves the modulation of JunD, a member of the AP-1 transcription factor family. THC activates JunD both by upregulating gene expression and by translocating the protein to the nuclear compartment, and these events are accompanied by a decrease in cell proliferation. Of interest, neither JunD activation nor proliferation inhibition was observed in human non-tumour mammary epithelial cells exposed to THC. We confirmed the importance of JunD in THC action by RNA interference and genetic ablation. Thus, in both JunD-silenced human breast cancer cells and JunD knockout mice-derived immortalized fibroblasts, the antiproliferative effect exerted by THC was significantly diminished. Gene array and siRNA experiments support that the cyclin-dependent kinase inhibitor p27 and the tumour suppressor gene testin are candidate JunD targets in cannabinoid action. In addition, our data suggest that the stress-regulated protein p8 participates in THC antiproliferative action in a JunD-independent manner. In summary, this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.

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Acknowledgements

We are indebted to the personnel of the Genomics Unit (Complutense University) for expert advice on RT-qPCR experiments, and to the members of our laboratories for technical support and critical discussions on this work, especially to M Salazar. C Sanchez and G Moreno-Bueno are researchers of the ‘Ramon y Cajal Program’ of the Spanish Ministry of Education and Science. MM Caffarel is the recipient of a fellowship from the Spanish Ministry of Education and Science. This work was supported by grants from Fondo de Investigaciones Sanitarias (C Sanchez and J Palacios), Fundacion Mutua Madrileña (C Sanchez), Spanish Ministry of Education and Science (J Palacios and M Guzman), ISCIII-RETIC (J Palacios), Comunidad de Madrid (M Guzman) and Inserm Avenir, Institut Curie and Fondation de France (F Mechta-Grigoriou).

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Correspondence to C Sanchez.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Caffarel, M., Moreno-Bueno, G., Cerutti, C. et al. JunD is involved in the antiproliferative effect of Δ9-tetrahydrocannabinol on human breast cancer cells. Oncogene 27, 5033–5044 (2008). https://doi.org/10.1038/onc.2008.145

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Keywords

  • cannabinoids
  • breast cancer
  • JunD
  • AP-1
  • p27
  • testin

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