Phenolic Cannabinoids Inhibit Cancer Cell Growth

Cannabinoids Induce Cancer Cell Proliferation via Tumor Necrosis Factor α-Converting Enzyme (TACE/ADAM17)-Mediated Transactivation of the Epidermal Growth Factor Receptor
  1. Stefan Hart, 
  2. Oliver M. Fischer, and 
  3. Axel Ullrich
+Author Affiliations

  1. Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany

Abstract Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite.

Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells.

Here, we demonstrate that anandamide, Δ9-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity.

EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling.

Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor α converting enzyme (TACE/ADAM17).

Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.


Footnotes
  • Grant support: O. Fischer has been supported by a Boehringer Ingelheim Fonds Ph.D. scholarship.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
  • Received November 28, 2003.
  • Revision received January 27, 2004.
  • Accepted February 4, 2004.

©2004 American Association for Cancer Research


SOURCE: http://cancerres.aacrjournals.org/content/64/6/1943.short