Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7


  • Bakiri L, Matsuo K, Wisniewska M, Wagner EF, Yaniv M . (2002). Promoter specificity and biological activity of tethered AP-1 dimers. Mol Cell Biol 22: 4952–4964.

    CAS  Article  Google Scholar 

  • Berdyshev EV, Schmid PC, Krebsbach RJ, Hillard CJ, Huang C, Chen N et al. (2001). Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem J 360: 67–75.

    CAS  Article  Google Scholar 

  • Blazquez C, Carracedo A, Barrado L, Real PJ, Fernandez-Luna JL, Velasco G et al. (2006). Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 20: 2633–2635.

    CAS  Article  Google Scholar 

  • Caffarel MM, Sarrio D, Palacios J, Guzman M, Sanchez C . (2006). Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res 66: 6615–6621.

    CAS  Article  Google Scholar 

  • Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G et al. (2006a). Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 66: 6748–6755.

    CAS  Article  Google Scholar 

  • Carracedo A, Lorente M, Egia A, Blazquez C, Garcia S, Giroux V et al. (2006b). The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 9: 301–312.

    CAS  Article  Google Scholar 

  • De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M et al. (1998). The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci USA 95: 8375–8380.

    CAS  Article  Google Scholar 

  • Drusco A, Zanesi N, Roldo C, Trapasso F, Farber JL, Fong LY et al. (2005). Knockout mice reveal a tumor suppressor function for Testin. Proc Natl Acad Sci USA 102: 10947–10951.

    CAS  Article  Google Scholar 

  • Eferl R, Wagner EF . (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3: 859–868.

    CAS  Article  Google Scholar 

  • Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D et al. (2004). JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 118: 781–794.

    CAS  Article  Google Scholar 

  • Giuliano M, Calvaruso G, Pellerito O, Portanova P, Carlisi D, Vento R et al. (2006). Anandamide-induced apoptosis in Chang liver cells involves ceramide and JNK/AP-1 pathway. Int J Mol Med 17: 811–819.

    CAS  PubMed  Google Scholar 

  • Guzman M . (2003). Cannabinoids: potential anticancer agents. Nat Rev Cancer 3: 745–755.

    CAS  Article  Google Scholar 

  • Guzman M, Duarte MJ, Blazquez C, Ravina J, Rosa MC, Galve-Roperh I et al. (2006). A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95: 197–203.

    CAS  Article  Google Scholar 

  • Hampson AJ, Grimaldi M, Axelrod J, Wink D . (1998). Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95: 8268–8273.

    CAS  Article  Google Scholar 

  • Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J . (2000). Neuroprotective antioxidants from marijuana. Ann NY Acad Sci 899: 274–282.

    CAS  Article  Google Scholar 

  • Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA . (2004). Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89: 134–141.

    CAS  Article  Google Scholar 

  • Lallemand D, Spyrou G, Yaniv M, Pfarr CM . (1997). Variations in Jun and Fos protein expression and AP-1 activity in cycling, resting and stimulated fibroblasts. Oncogene 14: 819–830.

    CAS  Article  Google Scholar 

  • Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L et al. (2006). Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318: 1375–1387.

    CAS  Article  Google Scholar 

  • Maccarrone M, Di Rienzo M, Battista N, Gasperi V, Guerrieri P, Rossi A et al. (2003). The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. J Biol Chem 278: 33896–33903.

    CAS  Article  Google Scholar 

  • Malumbres M, Barbacid M . (2001). To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1: 222–231.

    CAS  Article  Google Scholar 

  • Mechta F, Lallemand D, Pfarr CM, Yaniv M . (1997). Transformation by ras modifies AP1 composition and activity. Oncogene 14: 837–847.

    CAS  Article  Google Scholar 

  • Mechta-Grigoriou F, Gerald D, Yaniv M . (2001). The mammalian Jun proteins: redundancy and specificity. Oncogene 20: 2378–2389.

    CAS  Article  Google Scholar 

  • Pfarr CM, Mechta F, Spyrou G, Lallemand D, Carillo S, Yaniv M . (1994). Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell 76: 747–760.

    CAS  Article  Google Scholar 

  • Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A . (2006). Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281: 14841–14851.

    CAS  Article  Google Scholar 

  • Sarnataro D, Pisanti S, Santoro A, Gazzerro P, Malfitano AM, Laezza C et al. (2006). The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol Pharmacol 70: 1298–1306.

    CAS  Article  Google Scholar 

  • Stickeler E, Kittrell F, Medina D, Berget SM . (1999). Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene 18: 3574–3582.

    CAS  Article  Google Scholar 

  • van Dam H, Duyndam M, Rottier R, Bosch A, de Vries-Smits L, Herrlich P et al. (1993). Heterodimer formation of cJun and ATF-2 is responsible for induction of c-jun by the 243 amino acid adenovirus E1A protein. EMBO J 12: 479–487.

    CAS  Article  Google Scholar 

  • Weitzman JB, Fiette L, Matsuo K, Yaniv M . (2000). JunD protects cells from p53-dependent senescence and apoptosis. Mol Cell 6: 1109–1119.

    CAS  Article  Google Scholar 

  • Zhao Q, He Z, Chen N, Cho YY, Zhu F, Lu C et al. (2005). 2-Arachidonoylglycerol stimulates activator protein-1-dependent transcriptional activity and enhances epidermal growth factor-induced cell transformation in JB6 P+ cells. J Biol Chem 280: 26735–26742.

    CAS  Article  Google Scholar 

Download references


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).

Author information

Authors and Affiliations


Corresponding author

Correspondence to C Sanchez.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


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

Further reading


Quick links