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.
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.
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DOI：
10.18632/oncotarget.5822
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发表时间：
2015-12-15
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影响因子：
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通讯作者：
Podesta EJ
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文献类型：
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作者：
Orlando UD;Castillo AF;Dattilo MA;Solano AR;Maloberti PM;Podesta EJ
虽然酰基辅酶A合成酶4（ACSL 4）在介导侵袭性表型中的作用已被广泛接受，但关于ACSL 4增加肿瘤生长和进展的早期步骤的证据很少。在这项研究中，通过使用四环素Tet-Off系统（MCF-7 Tet-Off/ACSL 4）用ACSL 4稳定转染MCF-7细胞，我们将mTOR途径确定为ACSL 4表达的主要特异性特征之一，并证明了脂氧合酶途径部分参与mTOR的激活。ACSL 4对mTOR信号传导作用的特异性也通过多西环素抑制MCF-7 Tet-Off/ACSL 4细胞中的ACSL 4表达、通过ACSL 4在非侵袭性T47 D乳腺癌细胞系中的表达以及通过敲低该酶在组成型表达ACSL 4的MDA-MB-231乳腺癌细胞中的表达来确定。ACSL 4调节mTOR途径（mTORC 1/2）的两种复合物的组分，沿着上游调节物和底物。我们发现mTOR抑制剂雷帕霉素和ACSL 4抑制剂罗格列酮可以联合作用抑制细胞生长。此外，我们证明了罗格列酮和雌激素受体α（ERα）抑制剂他莫昔芬联合使用对细胞生长抑制的协同作用。值得注意的是，这种协同效应在体外和体内的三阴性MDA-MB-231细胞中也是明显的。这些结果表明，ACSL 4可能是恢复无病生存期和总生存期预后不良的肿瘤的肿瘤激素依赖性的靶点，其中没有有效的特异性靶向治疗。
Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. 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 the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined 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 by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates. We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo. These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available.