Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer

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

Oncotarget

Impact Journals

Año: 2015 vol. 6 p. 42632 - 42650

Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressivephenotype is well accepted, there is little evidence as to the early steps through whichACSL4 increases tumor growth and progression. In this study, and by means of the stabletransfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 TetOff/ACSL4),we identify the mTOR pathway as one of the main specific signatures ofACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathwayin the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is alsodetermined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells,by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and byknocking down this enzyme expression in the MDA-MB-231 breast cancer cells, whichconstitutively express ACSL4. ACSL4 regulates components of the two complexes of themTOR pathway (mTORC1/2), along with upstream regulators and substrates.We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone canact in combination to inhibit cell growth. In addition, we demonstrate a synergisticeffect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, anestrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evidentin the triple negative MDA-MB-231 cells in vitro and in vivo.These results suggest that ACSL4 could be a target to restore tumor hormonedependence in tumors with poor prognosis for disease-free and overall survival, inwhich no effective specifically targeted therapy is readily available.