Molecular mechanism of anandamide-induced apoptosis in non-melanoma skin cancer.

Abstract

Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. The absence of selective toxicity is the major problem associated with chemotherapeutic and radiation therapy for NMSCs. The goal of the present study was to determine the molecular mechanism of action of a potential selective treatment for NMSC, arachidonoyl ethanolamide [AEA, (also known as anandamide)]. Our research revealed that two factors provide AEA with its selective toxicity, the elevated cyclooxygenase-2 (COX-2) levels and the activated endoplasmic reticulum (ER) stress signaling in tumorigenic keratinocytes which differentiates them from normal cells. COX-2 is an enzyme that promotes tumor development by synthesizing E-series prostaglandins (PGs) that promote cell proliferation. Selective inhibition of COX-2 is successfully used in treatment of skin cancer. Rather than inhibiting COX-2, the novel approach of exploiting the overexpression of COX-2 was utilized. In tumorigenic keratinocytes, AEA was metabolized by COX-2 to cytotoxic J-series prostaglandin-ethanolamides (PGJ2-EAs) that are structurally distinct from arachidonic acid (AA)-derived J-series PGs. This data is novel and to the candidate's knowledge, this is the first report showing that PGJ2-EAs are produced as an AEA metabolic product. Furthermore, several studies showed that J-series PGs derived from AA induce oxidative stress, ER stress and apoptosis. Therefore, the candidate hypothesized that AEA is metabolized to PGJ2-EAs, which induce oxidative stress followed by ER stress and ultimately apoptosis as a novel mechanism of action of AEA. The candidate also took advantage of evidence, which shows that ER stress is moderately elevated in tumor cells when compared to normal cells. Under these circumstances, the exposure of cells to agents that induce additional stress is expected to cause overwhelming ER stress and subsequently apoptosis selectively in tumor cells. Indeed, the candidate determined that AEA induced ER stress-mediated apoptosis in COX-2 expressing tumor cells but not in normal cells. Hence, the present study provides an alternative strategy for topical treatment of NMSCs that will be selectively cytotoxic to cancer cells but not detrimental to normal, healthy surrounding cells.