Inhibition of tumor growth, steroidogenesis, hormone and drugs resistance by an acyl-CoA synthetase 4 new inhibitor

CASTILLO AF; PRADA JG; SZAJNMAN S; RODRIGUEZ JD; ORLANDO UD; DATTILO MA; LORENZANO MENNA P; PODESTA EJ; MALOBERTI PM; SOLANO AR; GOMEZ DE

Salta

Congreso; LV Annual SAIB Meeting and XIV PABMB Congress; 2019

Sociedad Argentina de Investigaciones Bioquímica y de Biología Molecular (SAIB)

Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme A ligase family taking part in arachidonic acid metabolism. This enzyme is involved in cancer development, particularly in breast and prostate cancers, where a correlation between its high expression and tumor cell aggressiveness has been found. Functionally, it was shown that ACSL4 is part of the mechanism responsible for increased breast and prostate cancer cell proliferation, invasion and migration. ACSL4 is involved in the regulation of several signal transduction mechanisms including mTOR pathway and furthermore increase the expression of proteins involved in drugs resistance.Another relevant property of this enzyme is its participation as an essential protein in the activation of cholesterol transport from the external to the internal mitochondrial membrane, the regulatory and rate-limiting step in the syntheses of all steroids. The development of selective inhibitors for ACSL4 which may inhibit tumor growth and steroidogenesis may be an important tool in the prevention and treatment of breast and prostate cancers expressing ACSL4.In this work we have developed and characterized a new ACSL4 inhibitor, PRGL493. An ACSL4 homology model was generated by MODELLER and a docking based virtual screening was performed. The selected compound was modified to improve particularly solubility properties and fully characterized through nuclear magnetic resonance and mass spectroscopy. We demonstrated that PRGL493 was effective in reducing AA-CoA levels, product of ACSL4 activity, in a cell free assay system using recombinant protein and in intact cells using cells models for steroidogenesis and tumor growth. Our compound inhibited cell proliferation and migration of highly aggressive human breast and prostate cancer cell lines (MDA-MB-231 and PC-3 respectively) and in vivo using the Chick Embryo Chorioallantoic Membrane model assay.Also, PRGL493 inhibited steroid synthesis both in vitro in Leydig, adrenal and PC-3 prostate cancer cells and in vivo in a mouse model, inhibiting cholesterol transport o the inner mitochondrial membrane and thus preventing steroid accumulation.Moreover, the inhibitor produced sensitization to hormonal and chemotherapeutic treatment. The combination of PRGL493 with tamoxifen, cisplatin, doxorubicin or paclitaxel in MDA-MB-231 cells, or with docetaxel in PC-3 cells showed a synergistic effect on the inhibition of cell proliferation.The results show that ACSL4 is an essential target for breast and prostate cancer therapy. These findings open an important route to treat these tumors which may lead to the development of rational cancer treatment and continue to lead to the introduction of the combination of chemotherapy to specific other agents.