15-deoxy, Δ12,14-prostaglandin J2-ethanolamide, also known as 15-deoxy, Δ12,14-prostamide J2 (15d-PMJ2) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by cyclooxygenase-2 (COX-2). 15d-PMJ2 preferentially induced cell death and apoptosis in tumorigenic A431 keratinocytes and B16F10 melanoma cells compared to non-tumorigenic HaCaT keratinocytes and Melan-A melanocytes. Activation of the ER stress execution proteins, PERK and CHOP10, was evaluated to determine if this process was involved in 15d-PMJ2 cell death. 15d-PMJ2 increased the phosphorylation of PERK and expression of CHOP10 in tumorigenic but not non-tumorigenic cells. The known ER stress inhibitors, salubrinal and 4-phenylbutaric acid significantly inhibited 15d-PMJ2 mediated apoptosis, suggesting ER stress as a primary apoptotic mediator. Furthermore, the reactive double bond present within the cyclopentenone structure of 15d-PMJ2 was identified as a required moiety for the induction of ER stress apoptosis. The effect of 15d-PMJ2 on B16F10 melanoma growth was also evaluated by dosing C57BL/6 mice with 0.5mg/kg 15d-PMJ2. Tumors of animals treated with 15d-PMJ2 exhibited significantly reduced growth and mean weights compared to vehicle and untreated animals. TUNEL and immunohistochemical analysis of tumor tissues showed significant cell death and ER stress in tumors of 15d-PMJ2 treated compared to control group animals. Taken together, these findings suggest that the novel prostamide, 15d-PMJ2, possesses potent anti-tumor activity in vitro and in vivo.
- Received July 22, 2016.
- Revision received January 17, 2017.
- Accepted February 17, 2017.
- Copyright ©2017, American Association for Cancer Research.