FDXR drives primary and endocrine-resistant tumor cell growth in ER+ breast cancer via CPT1A-mediated fatty acid oxidation.
FDXR drives primary and endocrine-resistant tumor cell growth in ER+ breast cancer via CPT1A-mediated fatty acid oxidation.
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FDXR通过CPT1A介导的脂肪酸氧化驱动ER+乳腺癌中的原发性和内分泌肿瘤细胞生长。
DOI：
10.3389/fonc.2023.1105117
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发表时间：
2023
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
大多数表达雌激素受体（ER）的乳腺癌（BC）表现出内分泌抵抗。我们以前的研究表明，铁氧还蛋白还原酶（FDXR）促进线粒体功能和ER+乳腺肿瘤的发生。但其内在机制尚不清楚。利用基于液相色谱（LC）串联质谱（MS/MS）的代谢物分析来揭示FDXR调节的代谢物。利用RNA微阵列来确定FDXR的潜在下游靶点。Seahorse XF 24分析仪分析FAO介导的耗氧率（OCR）。使用Q-PCR和蛋白质印迹分析来测量FDXR和CPT 1A的表达水平。MTS、2D集落形成和锚定非依赖性生长测定用于评价FDXR或药物治疗对原代或内分泌抗性乳腺癌细胞的肿瘤细胞生长的影响。我们发现FDXR的消耗通过抑制CPT 1A表达来抑制脂肪酸氧化（FAO）。内分泌治疗增加了FDXR和CPT 1A的表达水平。此外，我们发现FDXR或FAO抑制剂etomoxir处理的耗尽减少了原发性和内分泌抗性乳腺癌细胞的生长。在治疗上，内分泌治疗与FAO抑制剂etomoxir相结合可协同抑制原发性和内分泌抵抗性乳腺癌细胞的生长。我们揭示了FDXR-CPT 1A-FAO信号轴对于原发性和内分泌耐药乳腺癌细胞生长至关重要，从而提供了一种潜在的针对ER+乳腺癌内分泌耐药的联合治疗。
The majority of breast cancers (BCs) expressing estrogen receptor (ER) have shown endocrine resistance. Our previous study demonstrated that ferredoxin reductase (FDXR) promoted mitochondrial function and ER+ breast tumorigenesis. But the underlying mechanism is not clear. Liquid chromatography (LC) tandem mass spectrometry (MS/MS)-based metabolite profiling was utilized to reveal the metabolites regulated by FDXR. RNA microarray was utilized to determine the potential downstream targets of FDXR. Seahorse XF24 analyzer was performed to analyze the FAO-mediated oxygen consumption rate (OCR). Q-PCR and western blotting assays were used to measure expression levels of FDXR and CPT1A. MTS, 2D colony formation and anchorage-independent growth assays were used to evaluate the effects of FDXR or drug treatments on tumor cell growth of primary or endocrine-resistant breast cancer cells. We found that depletion of FDXR inhibited fatty acid oxidation (FAO) by suppressing CPT1A expression. Endocrine treatment increased the expression levels of both FDXR and CPT1A. Further, we showed that depletion of FDXR or FAO inhibitor etomoxir treatment reduced primary and endocrine-resistant breast cancer cell growth. Therapeutically, combining endocrine therapy with FAO inhibitor etomoxir synergistically inhibits primary and endocrine-resistant breast cancer cell growth. We reveal that the FDXR-CPT1A-FAO signaling axis is essential for primary and endocrine-resistant breast cancer cell growth, thus providing a potential combinatory therapy against endocrine resistance in ER+ breast cancer.
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影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen
影响因子：
45.3
作者：
Bachelot, Thomas;Bourgier, Celine;Pujade-Lauraine, Eric
通讯作者：
Pujade-Lauraine, Eric
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.
影响因子：
3.8
作者：
Beck, J. Thaddeus;Hortobagyi, Gabriel N.;Campone, Mario;Lebrun, Fabienne;Deleu, Ines;Rugo, Hope S.;Pistilli, Barbara;Masuda, Norikazu;Hart, Lowell;Melichar, Bohuslav;Dakhil, Shaker;Geberth, Matthias;Nunzi, Martina;Heng, Daniel Y. C.;Brechenmacher, Thomas;El-Hashimy, Mona;Douma, Shyanne;Ringeisen, Francois;Piccart, Martine
通讯作者：
Piccart, Martine
DOI：
10.2147/dddt.s137783
发表时间：
2018
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Corona SP;Generali D
通讯作者：
Generali D