Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells.
This study was designed to determine the molecular mechanisms underlying the anti-proliferative effect of the endocannabinoid anandamide on highly invasive human breast cancer cells, MDA-MB-231. We show that a metabolically stable analogue of anandamide, Met-F-AEA, induces an S phase growth arrest correlated with Chk1 activation, Cdc25A degradation and suppression of Cdk2 activity. These findings demonstrate that Met-F-AEA induced cell cycle blockade relies on modulated expression and activity of key S phase regulatory proteins. The observed mechanism of action, already reported for well-known chemotherapeutic drugs, provides strong evidence for a direct role of anandamide related compounds in the activation of cell cycle checkpoints.
Laezza
Chiara
C
IEOS CNR, Napoli, Italy. chilaez@hotmail.com
Pisanti
Simona
S
Crescenzi
Elvira
E
Bifulco
Maurizio
M
D001095:Arachidonic Acids / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D063388:Endocannabinoids; D005260:Female; D006801:Humans; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; C078814:anandamide