ACYL-COA SYNTHETASE-4 A NEW TARGET TO RESTORE TUMOR DRUG SENSITIVITY IN TRIPLE NEGATIVE BREAST CANCER.

ORLANDO, ULISES; SOLANO, ANGELA; MALOBERTI, PAULA; CASTILLO, ANA FERNANDA; PODESTÁ, ERNESTO J

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de BioCiencias; 2017

SAA, SAFE, SAFIS, SAH, SAIB, SAIC, SAP, SA de Biofísica, SA de Biología, SAI

The design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors. The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more that detect and eject anticancer drugs from cells, We have previously shown that the acyl-CoA synthetase 4 (ACSL4) play a role in the hormone resistance to therapy, the aim of the present work is to study the role ofACSL4 on mechanisms of cancer drug resistance. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 Tet- Off/ACSL4), we identify ACSL4-responsive drug resistance genes (13) that were significantly and differentially expressed in MCF-7 Tet-Off/ACSL4 compared to MCF-7 Tet-Off empty vector (log2 fold change 1.6). The specificity of ACSL4 action is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells. We further show that the minimal doses of the , cisplatin, doxirubicin and paclitaxel which produced a significant (p 0.001) inhibition on cell proliferation was significantly higher in the ACSL4 expressing cells. ACSL4 inhibitor triascin C and rosiglitazone can act in combination with the chemotherapeutic agents to inhibit cell growth. In addition, we demonstrate a high cell growth inhibition by these combinations. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vivo. These results suggest that ACSL4 could be a target to restore tumor drug sensitivity in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available.