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

  • BMC Cancer. 2016 Jul 13:16:458. doi: 10.1186/s12885-016-2499-3.
Seok-Woo Park  1 ,  J Hun Hah  1  2  3 ,  Sang-Mi Oh  1 ,  Woo-Jin Jeong  4 ,  Myung-Whun Sung  5  6  7  8
Affiliations
  • 1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
  • 2. Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea.
  • 3. Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
  • 4. Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seoul, South Korea.
  • 5. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. [email protected].
  • 6. Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea. [email protected].
  • 7. Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea. [email protected].
  • 8. Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul National University Hospital, Seoul, South Korea. [email protected].
PMID: 27411387 DOI: 10.1186/s12885-016-2499-3
Abstract

Background: 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.

Methods and results: 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.

Conclusions: 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.

Keywords
5-lipoxygenase; DHEA; Endocannabinoid; Head and neck cancer; NALA; ROS.
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