New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

• Published in: Cellular and molecular life sciences : CMLS Vol. 78; no. 6; pp. 2893 - 2910
• Main Authors: Castillo, Ana F., Orlando, Ulises D., Maloberti, Paula M., Prada, Jesica G., Dattilo, Melina A., Solano, Angela R., Bigi, María M., Ríos Medrano, Mayra A., Torres, María T., Indo, Sebastián, Caroca, Graciela, Contreras, Hector R., Marelli, Belkis E., Salinas, Facundo J., Salvetti, Natalia R., Ortega, Hugo H., Lorenzano Menna, Pablo, Szajnman, Sergio, Gomez, Daniel E., Rodríguez, Juan B., Podesta, Ernesto J.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2021; Springer Nature B.V
• Subjects: Animal models; Animals; Arachidonic acid; Binding Sites; Biochemistry; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Biology; Cell culture; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Coenzyme A Ligases - antagonists & inhibitors; Coenzyme A Ligases - metabolism; Drug resistance; Drug Resistance, Neoplasm; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fatty acids; Female; Gene expression; Homology; Humans; Life Sciences; Male; Mass spectroscopy; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; NMR; Nuclear magnetic resonance; Original; Original Article; Prostate; Prostate - cytology; Prostate - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Signal transduction; Steroidogenesis; Steroids; Steroids - blood; Synthesis; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Anti-hormone treatment resistance; Chemotherapy resistance; Triple negative breast cancer; Castration resistant prostate cancer
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-020-03679-5

Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme-A family taking part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in the development of tumor aggressiveness in breast and prostate tumors through the regulation of various signal transduction pathways. Here, a bioinformatics analysis shows that the ACSL4 gene expression and proteomic signatures obtained using a cell model was also observed in tumor samples from breast and cancer patients. A well-validated ACSL4 inhibitor, however, has not been reported hindering the full exploration of this promising target and its therapeutic application on cancer and steroidogenesis inhibition. In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis.