Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells.
Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells.
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DOI：
10.1371/journal.pone.0015540
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发表时间：
2010-11-11
期刊：
影响因子：
3.7
通讯作者：
Podestá EJ
中科院分区：
文献类型：
--
作者：
Maloberti PM;Duarte AB;Orlando UD;Pasqualini ME;Solano AR;López-Otín C;Podestá EJ
酰基辅酶A合成酶4（ACSL 4）在乳腺癌、结肠癌和肝细胞癌中增加。ACSL 4主要将花生四烯酸（AA）转化为花生四烯酸酰辅酶A，降低细胞内游离AA水平，这与肿瘤发生中AA代谢物的需求相矛盾。因此，ACSL 4的因果作用仍未确立。本研究旨在确定ACSL 4在乳腺癌细胞AA代谢途径中的作用。第一个新发现是ACSL 4调节MDA-MB-231细胞中环氧合酶-2（考克斯-2）的表达和前列腺素的产生。我们还发现ACSL 4在高度侵袭性的MDA-MB-231乳腺癌细胞中显著上调。就其过表达和抑制而言，ACSL 4在控制侵袭性表型中起因果作用。这些结果通过用Tet-off ACSL 4载体稳定转染的MCF-7细胞的侵袭行为增加得到证实。同时，另一个重要的发现是，线粒体内AA水平显着较高的侵略性细胞。因此，ACSL 4对AA的酯化使AA在线粒体中的释放区室化，这是一种用于驱动脂肪酸的特异性脂氧合酶代谢的机制。据我们所知，这是第一份ACSL 4表达控制AA的脂氧合酶和环氧合酶代谢的报告。因此，这种功能性相互作用代表了调节癌细胞增殖和转移潜力的整合系统。因此，开发从ACSL 4、脂氧合酶和考克斯-2协同作用中获益的联合治疗可能允许降低药物剂量并避免副作用。
The acyl-CoA synthetase 4 (ACSL4) is increased in breast cancer, colon and hepatocellular carcinoma. ACSL4 mainly esterifies arachidonic acid (AA) into arachidonoyl-CoA, reducing free AA intracellular levels, which is in contradiction with the need for AA metabolites in tumorigenesis. Therefore, the causal role of ACSL4 is still not established. This study was undertaken to determine the role of ACSL4 in AA metabolic pathway in breast cancer cells. The first novel finding is that ACSL4 regulates the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin in MDA-MB-231 cells. We also found that ACSL4 is significantly up-regulated in the highly aggressive MDA-MB-231 breast cancer cells. In terms of its overexpression and inhibition, ACSL4 plays a causal role in the control of the aggressive phenotype. These results were confirmed by the increase in the aggressive behaviour of MCF-7 cells stably transfected with a Tet-off ACSL4 vector. Concomitantly, another significant finding was that intramitochondrial AA levels are significantly higher in the aggressive cells. Thus, the esterification of AA by ACSL4 compartmentalizes the release of AA in mitochondria, a mechanism that serves to drive the specific lipooxygenase metabolization of the fatty acid. To our knowledge, this is the first report that ACSL4 expression controls both lipooxygenase and cyclooxygenase metabolism of AA. Thus, this functional interaction represents an integrated system that regulates the proliferating and metastatic potential of cancer cells. Therefore, the development of combinatory therapies that profit from the ACSL4, lipooxygenase and COX-2 synergistic action may allow for lower medication doses and avoidance of side effects.
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影响因子：
11.2
作者：
Gutierrez-Fernandez, Ana;Fueyo, Antonio;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
影响因子：
2.1
作者：
Castillo, F;Cano, F;Maciel, FC
通讯作者：
Maciel, FC
影响因子：
3.8
作者：
Larkins TL;Nowell M;Singh S;Sanford GL
通讯作者：
Sanford GL
DOI：
10.1016/j.bbapap.2007.03.012
发表时间：
2007-05-01
影响因子：
3.2
作者：
Distler, Anne M.;Kerner, Janos;Hoppel, Charles L.
通讯作者：
Hoppel, Charles L.
影响因子：
2.8
作者：
Han, ZQ;Slack, RS;Papadopoulos, V
通讯作者：
Papadopoulos, V