Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells.
Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells.
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脂肪酸氧化和自噬促进了内氧化昔夫尼的耐药性，并抵消AKT抑制在ER阳性乳腺癌细胞中的作用。
DOI：
10.1093/jmcb/mjab018
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发表时间：
2021-09-11
影响因子：
5.5
通讯作者：
Maki CG
中科院分区：
文献类型：
--
作者：
Duan L;Calhoun S;Shim D;Perez RE;Blatter LA;Maki CG
他莫昔芬（TAM）是雌激素受体阳性（ER+）乳腺癌（BC）的一线内分泌治疗药物。然而，获得性耐药发生在大约50%的病例中。同时，尽管PI 3 K/AKT/mTOR通路是治疗内分泌治疗难治性患者的可行靶点，但存在复杂的信号反馈回路，这可以抵消该通路抑制剂的有效性。在这里，我们使用免疫印迹、定量聚合酶链反应和Agilent Seahorse XF分析仪分析了ER+ MCF 7 BC细胞系及其TAM耐药衍生物中的信号通路和代谢，这些衍生物对内昔芬具有共同耐药性。我们发现，激活AKT和能量敏感激酶AMPK增加TAM和内毒素耐药细胞。此外，ERRα/PGC-1β及其靶基因MCAD和CPT-1的表达增加并受到AMPK的调节，这与TAM抗性细胞中脂肪酸氧化（FAO）和自噬的增加相一致。抑制AKT反馈激活AMPK和ERRα/PGC-1β-MCAD/CPT-1，从而增加FAO和自噬，抵消内昔芬和AKT抑制剂的治疗作用。因此，我们的研究结果表明，在TAM抗性细胞中，AKT和AMPK的活化随着代谢重编程和自噬的增加而增加。同时抑制AKT和FAO/自噬是使耐药细胞对内昔芬完全敏感所必需的。
Tamoxifen (TAM) is the first-line endocrine therapy for estrogen receptor-positive (ER+) breast cancer (BC). However, acquired resistance occurs in ∼50% cases. Meanwhile, although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients, complex signaling feedback loops exist, which can counter the effectiveness of inhibitors of this pathway. Here, we analyzed signaling pathways and metabolism in ER+ MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting, quantitative polymerase chain reaction, and the Agilent Seahorse XF Analyzer. We found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant cells. Furthermore, ERRα/PGC-1β and their target genes MCAD and CPT-1 were increased and regulated by AMPK, which coincided with increased fatty acid oxidation (FAO) and autophagy in TAM-resistant cells. Inhibition of AKT feedback-activates AMPK and ERRα/PGC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT inhibitors. Therefore, our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells. Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.
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影响因子：
16.6
作者：
Han F;Li CF;Cai Z;Zhang X;Jin G;Zhang WN;Xu C;Wang CY;Morrow J;Zhang S;Xu D;Wang G;Lin HK
通讯作者：
Lin HK
影响因子：
3.8
作者：
Bostner, Josefine;Karlsson, Elin;Pandiyan, Muneeswaran J.;Westman, Hanna;Skoog, Lambert;Fornander, Tommy;Nordenskjold, Bo;Stal, Olle
通讯作者：
Stal, Olle
DOI：
10.1042/bj20131344
发表时间：
2014-04-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Hawley SA;Ross FA;Gowans GJ;Tibarewal P;Leslie NR;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1161/hypertensionaha.111.174128
发表时间：
2011-10
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Hu X;Xu X;Lu Z;Zhang P;Fassett J;Zhang Y;Xin Y;Hall JL;Viollet B;Bache RJ;Huang Y;Chen Y
通讯作者：
Chen Y
影响因子：
3.4
作者：
Cartee, Gregory D.;Wojtaszewski, Jorgen F. P.
通讯作者：
Wojtaszewski, Jorgen F. P.