title: 5-lipoxygenase mediates docosahexaenoyl ethanolamide and N-arachidonoyl-L-alanine-induced reactive oxygen species production and inhibition of proliferation of head and neck squamous cell carcinoma cells.
abstract: Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA.
  
  
  
  DHEA and NALA were found to effectively inhibit HNSCC cell proliferation. These anti-proliferative effects seemed to be mediated in a cannabinoid receptor-independent manner, since the antagonist of cannabinoid receptor-1 (CB1) and vanilloid receptor-1 (VR1), two endocannabinoid receptors, did not reverse the ability of DHEA and NALA to induce cell death. Instead, we observed an increase in reactive oxygen species (ROS) production and a decrease of phosphorylated Akt as a result of DHEA and NALA treatment. Antioxidants efficiently reversed the inhibition of cell proliferation and the decrease of phosphorylated Akt induced by DHEA and NALA; inhibition of 5-lipoxygenase (5-LO), which is expected to be involved in DHEA- and NALA-degradation pathway, also partially blocked the ability of DHEA and NALA to inhibit cell proliferation and phosphorylated Akt. Interestingly, ROS production as a result of DHEA and NALA treatment was decreased by inhibition of 5-LO.
  
  
  
  From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Seok-Woo
authors.initials: SW
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea.|Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors.forename: J Hun
authors.initials: JH
authors.lastname: Hah
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Sang-Mi
authors.initials: SM
authors.lastname: Oh
authors.affiliation: Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seoul, South Korea.
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Jeong
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. mwsung@snu.ac.kr.|Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea. mwsung@snu.ac.kr.|Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea. mwsung@snu.ac.kr.|Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul National University Hospital, Seoul, South Korea. mwsung@snu.ac.kr.
authors.forename: Myung-Whun
authors.initials: MW
authors.lastname: Sung
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D001393:Azoles / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D063646:Carcinogenesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D063388:Endocannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D054833:Isoindoles; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D001393:Azoles; D016227:Benzoquinones; C571130:CNR1 protein, human; D063388:Endocannabinoids; D054833:Isoindoles; D016859:Lipoxygenase Inhibitors; C483476:N-arachidonoylalanine; C561061:N-docosahexaenoylethanolamide; D016566:Organoselenium Compounds; D010880:Piperidines; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C103505:AM 251; C042986:ebselen; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000409:Alanine; C063449:zileuton; D006918:Hydroxyurea
keywords: 5-lipoxygenase; DHEA; Endocannabinoid; Head and neck cancer; NALA; ROS