The expression level of CB1 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas.
BACKGROUND
Cannabinoids represent unique compounds for treating tumors, including astrocytomas. Whether CB(1) and CB(2) receptors mediate this therapeutic effect is unclear.


RESULTS
We generated astrocytoma subclones that express set levels of CB(1) and CB(2), and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to ERK1/2. In contrast, cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT. Remarkably, cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB(1), CB(2) and AKT, but still through a mechanism involving ERK1/2.


CONCLUSIONS
The high expression level of CB(1) and CB(2) receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics, unless AKT is concomitantly inhibited, or cannabinoids are applied at concentrations that bypass CB(1) and CB(2) receptors, yet still activate ERK1/2.
Cudaback
Eiron
E
Department of Pharmacology, University of Washington, Seattle, Washington, United States of America.
Marrs
William
W
Moeller
Thomas
T
Stella
Nephi
N
D017209:Apoptosis; D001254:Astrocytoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D015398:Signal Transduction
D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D048049:Extracellular Signal-Regulated MAP Kinases