http://jnci.oxfordjournals.org/cgi/content/abstract/djm268v1

Inhibition of Cancer Cell Invasion by Cannabinoids via Increased Expression 
of Tissue Inhibitor of Matrix Metalloproteinases-1

Robert Ramer, Burkhard Hinz
Affiliation of authors: Institute of Toxicology and Pharmacology, University 
of Rostock, Rostock, Germany

Background: Cannabinoids, in addition to having palliative benefits in 
cancer therapy, have been associated with anticarcinogenic effects. Although 
the antiproliferative activities of cannabinoids have been intensively 
investigated, little is known about their effects on tumor invasion.
Methods: Matrigel-coated and uncoated Boyden chambers were used to quantify 
invasiveness and migration, respectively, of human cervical cancer (HeLa) 
cells that had been treated with cannabinoids (the stable anandamide analog 
R(+)-methanandamide [MA] and the phytocannabinoid 9-tetrahydrocannabinol 
[THC]) in the presence or absence of antagonists of the CB1 or CB2 
cannabinoid receptors or of transient receptor potential vanilloid 1 (TRPV1) 
or inhibitors of p38 or p42/44 mitogen-activated protein kinase (MAPK) 
pathways. Reverse transcriptase-polymerase chain reaction (RT-PCR) and 
immunoblotting were used to assess the influence of cannabinoids on the 
expression of matrix metalloproteinases (MMPs) and endogenous tissue 
inhibitors of MMPs (TIMPs). The role of TIMP-1 in the anti-invasive action 
of cannabinoids was analyzed by transfecting HeLa, human cervical carcinoma 
(C33A), or human lung carcinoma cells (A549) cells with siRNA targeting 
TIMP-1. All statistical tests were two-sided.
Results: Without modifying migration, MA and THC caused a time- and 
concentration-dependent suppression of HeLa cell invasion through Matrigel 
that was accompanied by increased expression of TIMP-1. At the lowest 
concentrations tested, MA (0.1 µM) and THC (0.01 µM) led to a decrease in 
invasion (normalized to that observed with vehicle-treated cells) of 61.5% 
(95% CI = 38.7% to 84.3%, P < .001) and 68.1% (95% CI = 31.5% to 104.8%, P = 
.0039), respectively. The stimulation of TIMP-1 expression and suppression 
of cell invasion were reversed by pretreatment of cells with antagonists to 
CB1 or CB2 receptors, with inhibitors of MAPKs, or, in the case of MA, with 
an antagonist to TRPV1. Knockdown of cannabinoid-induced TIMP-1 expression 
by siRNA led to a reversal of the cannabinoid-elicited decrease in tumor 
cell invasiveness in HeLa, A549, and C33A cells.

Conclusion: Increased expression of TIMP-1 mediates an anti-invasive effect 
of cannabinoids. Cannabinoids may therefore offer a therapeutic option in 
the treatment of highly invasive cancers.

CONTEXT AND CAVEATS
Prior knowledge
Treatment with cannabinoids had been shown to reduce the invasiveness of 
cancer cells, but the cellular mechanisms underlying this effect were 
unclear.
Study design
Cancer cells treated with combinations of cannabinoids, antagonists of 
cannabinoid receptors, and siRNA to tissue inhibitor of matrix 
metalloproteinases-1 (TIMP-1) were assessed for invasiveness, protein 
expression, and activation of signal transduction pathways.
Contribution
The expression of TIMP-1 was shown to be stimulated by cannabinoid receptor 
activation and to mediate the anti-invasive effect of cannabinoids.
Implications
Clarification of the mechanism of cannabinoid action may help investigators 
to explore their therapeutic benefit.
Limitations
The relevance of the findings to the behavior of tumor cells in vivo remains 
to be determined.

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Slatts

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