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Arachidonoyl‐ethanolamide activates endoplasmic reticulum stress‐apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase‐2 and novel J‐series prostamides
Author(s) -
Soliman Eman,
Henderson Kate L.,
Danell Allison S.,
Van Dross Rukiyah
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22257
Subject(s) - unfolded protein response , apoptosis , biology , endoplasmic reticulum , cyclooxygenase , microbiology and biotechnology , cancer research , transfection , atf6 , endocrinology , cell culture , biochemistry , enzyme , genetics
Non‐melanoma skin cancer and other epithelial tumors overexpress cyclooxygenase‐2 (COX‐2), differentiating them from normal cells. COX‐2 metabolizes arachidonic acid to prostaglandins including, the J‐series prostaglandins, which induce apoptosis by mechanisms including endoplasmic reticulum (ER) stress. Arachidonoyl‐ethanolamide (AEA) is a cannabinoid that causes apoptosis in diverse tumor types. Previous studies from our group demonstrated that AEA was metabolized by COX‐2 to J‐series prostaglandins. Thus, the current study examines the role of COX‐2, J‐series prostaglandins, and ER stress in AEA‐induced apoptosis. In tumorigenic keratinocytes that overexpress COX‐2, AEA activated the PKR‐like ER kinase (PERK), inositol requiring kinase‐1 (IRE1), and activating transcription factor‐6 (ATF6) ER stress pathways and the ER stress apoptosis‐associated proteins, C/EBP homologous protein‐10 (CHOP10), caspase‐12, and caspase‐3. Using an ER stress inhibitor, it was determined that ER stress was required for AEA‐induced apoptosis. To evaluate the role of COX‐2 in ER stress‐apoptosis, HaCaT keratinocytes with low endogenous COX‐2 expression were transfected with COX‐2 cDNA or an empty vector and AEA‐induced ER stress‐apoptosis occurred only in the presence of COX‐2. Moreover, LC‐MS analysis showed that the novel prostaglandins, 15‐deoxyΔ 12,14 PGJ 2 ‐EA and Δ 12 PGJ 2 /PGJ 2 ‐EA, were synthesized from AEA. These findings suggest that AEA will be selectively toxic in tumor cells that overexpress COX‐2 due to the metabolism of AEA by COX‐2 to J‐series prostaglandin‐ethanolamides (prostamides). Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX‐2. © 2015 Wiley Periodicals, Inc.