1. ¹Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain
2. ²Department of Biochemistry, Instituto de Investigaciones Biomedicas 'Alberto Sols', Autonoma University, Madrid, Spain
3. ³Department of Pathology, Hospital Universitario Virgen del Rocio, Seville, Spain
4. ⁴Inserm U830, Institut Curie, Paris, France

Correspondence: Dr C Sanchez, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, C/Jose Antonio Novais 2, Madrid 28040, Spain. E-mail: cristina.sanchez@quim.ucm.es

Received 22 August 2007; Revised 16 January 2008; Accepted 3 April 2008; Published online 5 May 2008.

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 ⁹-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.