The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma.
The endocannabinoid system plays protective roles against the growth and the spreading of several types of carcinomas. Because estrogens regulate this system both in physiological states and cancer, in this paper we evaluated its involvement in endometrial carcinoma, a well-known estrogen-dependent tumor. To test whether the endocannabinoid system is expressed in endometrial cancer, tissue samples were collected both from 18 patients undergoing surgical treatment for endometrial adenocarcinoma and 16 healthy age-matched controls, and treated for Western blot and immunohistochemical analysis. Moreover, tissues were dounce homogenized and submitted to endocannabinoid measurement by liquid chromatography-mass spectrometry. To evaluate the physiological role of the endocannabinoid system, a human endometrial cancer cell-line (AN3CA) was used and transiently transfected with a plasmid containing the cDNA for the endocannabinoid receptor CB(2). Cells were incubated for 48 h with an agonist (JWH133) (10 mum) or antagonist (SR144528) (1 mum) of CB(2) 24 h after transfection, and cell proliferation was measured by the 3-[4,5-dimethyltiazol-2yl]-2,5 diphenyltetrazolium bromide formazan assay. In human endometrial carcinoma biopsies the expression of CB(2) receptor and the levels of its ligand, 2-arachidonoylglycerol increased, whereas monoacylglycerol lipase, an enzyme responsible for 2-arachidonoylglycerol degradation, was down-regulated. Immunohistochemical analysis revealed that CB(2) was overexpressed only in malignant endometrial cells. CB(2)-overexpressing AN3CA cells showed a significant reduction in cell vitality compared with parental AN3CA cells: incubation with the selective CB(2) antagonist SR144128 restored the viability of CB(2)-overexpressing cells to that of untransfected cells. In conclusion, the endocannabinoid system seems to play an important role in human endometrial carcinoma, and modulation of CB(2) activity/expression may account for a tumor-suppressive effect.
Department of Gynecology and Obstetrics and Pathophysiology of Human Reproduction, University of Naples Federico II, 80078 Naples, Italy.
Maurizio
M
Guida
Alessia
A
Ligresti
Daniele
D
De Filippis
Alessandra
A
D'Amico
Stefania
S
Petrosino
Mariateresa
M
Cipriano
Giuseppe
G
Bifulco
Sara
S
Simonetti
Pierangelo
P
Orlando
Luigi
L
Insabato
Carmine
C
Nappi
Attilio
A
Di Spiezio Sardo
Vincenzo
V
Di Marzo
Teresa
T
Iuvone
D000328:Adult; D001095:Arachidonic Acids / Q000378:metabolism*; D001706:Biopsy; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D063388:Endocannabinoids; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000473:pathology; D005260:Female; D005989:Glycerides / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D015854:Up-Regulation
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043885:Receptor, Cannabinoid, CB2; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases