Downregulation of GLI1- dependent survival pathway underlies arachidonic acid antitumoral activity

Abstract

Numerous studies have demonstrated a role for essential fatty acids (ePUFAs) during tumor evelopment. However, the molecularmechanism underlying this phenomenon remains elusive. Here, we defined a novel molecular mechanism explaining the ePUFA arachidonic acid (AA) anti-tumoral activity. We used in vivo and invitro assays to determine the effect of AA in primary tumor volume, lung micro-metastasis and apoptosis (TUNEL and Caspase 3/7activation) as well as gene expression (qRT-PCR and WB) andtranscriptional activity (Luciferase and ChIP assays). We observed a significant reduction in tumor volume and micro-metastasis incidence in AA-injected animals compared to the control group.Moreover, we demonstrated an increased apoptosis level in AA treated group in vivo and in vitro. Analysis of the mechanism showed that the AA treatment decreases the expression of the anti-apoptotic molecules Bcl-2 and Bfl-1/A1 by down-regulating their promoter activity. Moreover we found that the AA silencing of the oncogenic transcription factor GLI1 is the underling mechanism controlling Bcl-2 and Bfl-1/A1 expression. Finally, we demonstrated that AAinduced apoptosis can be rescued by overexpressing GLI1 in cancer cells. These results define a novel mechanism used by ePUFAs to inhibit tumor growth and suggest the use of AA for the development of new therapeutic approaches.