ACYL-COA SYNTHETASE 4: A NOVEL REGULATOR OF THE MTOR PATHWAY IN BREAST CANCER CELLS

ORLANDO ULISES; CASTILLO ANA FERNANADA; DATTILO MELINA; SOLANO ANGELA; MALOBERTI PAULA; PODESTA, ERNESTO J

Rosario

Congreso; L Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2014

Breast cancer comprises a heterogeneous group of diseases that vary in morphology, biology, behavior and response to therapy. Previous studies have identified an acyl-CoA syntethase 4 (ACSL4) expression which correlated with tumor progression in breast cancer. We have proven that cell transfection solely with ACSL4 cDNA renders a highly aggressive phenotype in vitro and in vivo. Although the role of ACSL4 in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth. Therefore, we have performed a massive in-depth mRNA sequencing approach and functional proteomic to identify gene expression and functional proteomic signatures specific to ACSL4 overexpression. ACSL4 displays a distinctive transcriptome and functional proteomic profile, and results show that the most significantly up-regulated gene networks include genes associated to the regulation of embryonic and tissue development, cellular movement and DNA replication and repair. Specific pathways such as AKT-mTOR-SP6 kinase and Wnt are functionally required for ACSL4 action. Finally, by means of a combination of ACSL4 and mTOR inhibitors, we demonstrate a synergistic effect in the inhibition of cell growth. ACSL4 is an upstream regulator of tumorigenic pathways. Our data provide novel insights into a combined pharmacological approach.