NFATc1-Dependent Downregulation of GLI1 Underlies Polyunsaturated Fatty Acids Cytotoxic Properties in Pancreatic Cancer

A. COMBA; PASQUALINI ME; IGUCHI, M.; VARA MESLER M; SILVA RA; GARCIA FERNANDEZ BARRENA M; TOLOSA EJ; ENRIQUEZ-HESLES, A.L.; VRABEL AL; ALMADA LA; MARKS DL; BOTTA B; DI MARCOTULIO L; ELLENRIEDER V; EYNARD A R; FERNANDEZ-ZAPICO M.E.

San Diego

Congreso; 46 th Annual Meeting of the American Pancreatic Association (APA); 2015

American Pancreatic Association (APA)

Numerous reports have demonstrated a growth inhibitory effect of PolyunsaturatedFatty Acids (PUFAs) in multiple tumors including pancreatic cancer.However, the molecular mechanisms modulating this phenomenon remainelusive. Here, we provide evidence of a novel anti-tumoral mechanism of thePUFA arachidonic acid (AA). In vivo and in vitro experiments showed thatAA treatment decreases tumor growth and metastasis, and increases apoptosis.Molecular analysis of this effect showed reduced expression of a subset of antiapoptoticproteins, BCL2, BFL1/A1 and 4-1BB inAA-treated cells.We demonstratedthat the downregulation of the transcription factor GLI1 is the underlyingmechanism controlling BCL2, BFL1/A1 and 4-1BB expression.Using chromatinimmunoprecipitation and expression studies, we demonstrated that GLI1binds to the promoter of these antiapoptotic molecules, and regulates their expression.Further characterization showed that AA regulates GLI1 expressionthrough the modulation of its promoter via NFATc1-mediated repression ofGLI1 transcription. AA promotes NFATc1 activation through an oxidative stress-Calcineurin dependent axis. Finally, we provide evidence that AA-induced apoptosis and gene repression can be inhibited by overexpressing GLI1 in AA-sensitive cells. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for the future PUFA-based therapeutic approaches.