ACYL-COA SYNTHETASE 4 MODULATES GLYCOLYTIC FUNCTION AND MITOCHONDRIAL METABOLISM IN BREAST CANCER CELLS

BENZO, YANINA; PRADA, JESICA G.; DATTILO, MELINA A.; LOPEZ, PAULA F.; CASTILLO, ANA F.; MORI SEQUEIROS GARCIA, M. MERCEDES; PODEROSO CECILIA; MALOBERTI, PAULA M.

Congreso; LXVII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2022

The relationship between cancer and mitochondrial function has been widely demonstrated. Mitochondrial dysfunction is associated with oncogenesis and cancer development mainly by the prevalence of anaerobic glycolysis even under normoxia (Warburg effect). In breast cancer, Acyl-CoA synthetase 4 (ACSL4), an enzyme involved in arachidonic acid metabolism, promotes tumor aggressiveness. Previously, we demonstrated in MCF-7 breast cancer cells that stable overexpression of ACSL4 significantly increases the levels of mitochondrial markers, mitochondrial activity and respiratory parameters such as proton leak, maximal respiration, and spare respiratory capacity (p˂ 0.05, p˂0.01) respective to control cells. The aim of this work is to determine whether glycolytic function and mitochondrial metabolism are modulated by ACSL4 in breast cancer cells. For this purpose, Seahorse XF Glycolysis Stress Test was carried out to measure extra acidification rate (ECAR) and glycolytic parameters. Our results showed a significant increase in glycolytic function, non- glycolytic acidification, and glycolysis (p˂0.05, p˂0.01) and an increase in glycolytic capacity in MCF-7 overexpressing ACSL4. Furthermore, ACSL4 induced a significant decrease in the percentage of glycolytic reserve (p˂ 0.05) relative to control cells. These results corroborate a role of ACSL4 in glycolytic function in MCF-7 breast cancer cells. Also, we observed a significant increase (p˂ 0.05) in mRNA levels of mitochondrial genes related to mitochondrial function such as NRF-1/2, UCP2 and ANT1 in MCF-7 overexpressing ACSL4 cells (p˂0.05). In conclusion, our work suggests that ACSL4 could confer an adaptive advantage to tumor cells by inducing glycolytic metabolism favoring tumor development and could protect mitochondria by promoting the expression of biogenesis genes. These results expand our knowledge of the role of ACSL4 in glycolytic function and metabolism of mitochondria in breast cancer cells.