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Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells
Journal of Molecular Cell Biology ( IF 5.5 ) Pub Date : 2021-03-23 , DOI: 10.1093/jmcb/mjab018
Lei Duan 1 , Sarah Calhoun 1 , Daeun Shim 1 , Ricardo E Perez 1 , Lothar A Blatter 2 , Carl G Maki 1
Affiliation  

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.

中文翻译:

脂肪酸氧化和自噬促进内多昔芬耐药并对抗 ER 阳性乳腺癌细胞中 AKT 抑制的作用

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,获得性耐药发生在约 50% 的病例中。同时,虽然 PI3K/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,可以对抗该通路抑制剂的有效性。在这里,我们使用免疫印迹、定量聚合酶链式反应和安捷伦 Seahorse XF 分析仪分析了 ER+ MCF7 BC 细胞系及其对内多昔芬共耐药的 TAM 耐药衍生物中的信号通路和代谢。我们发现 AKT 和能量感应激酶 AMPK 的激活在 TAM 和耐内昔芬细胞中增加。此外,ERRα/PGC-1β及其靶基因MCAD和CPT-1被AMPK增加和调节,这与 TAM 抗性细胞中脂肪酸氧化 (FAO) 和自噬的增加相吻合。抑制 AKT 反馈会激活 AMPK 和 ERRα/PGC-1β-MCAD/CPT-1,从而增加 FAO 和自噬,从而抵消 endoxifen 和 AKT 抑制剂的治疗效果。因此,我们的结果表明 AKT 和 AMPK 的激活随着代谢重编程和 TAM 抗性细胞的自噬增加而增加。同时抑制AKT和FAO/自噬对于使抗性细胞对内多昔芬完全敏感是必要的。我们的结果表明,随着代谢重编程和 TAM 抗性细胞的自噬增加,AKT 和 AMPK 的激活增加。同时抑制AKT和FAO/自噬对于使抗性细胞对内多昔芬完全敏感是必要的。我们的结果表明,随着代谢重编程和 TAM 抗性细胞的自噬增加,AKT 和 AMPK 的激活增加。同时抑制AKT和FAO/自噬对于使抗性细胞对内多昔芬完全敏感是必要的。
更新日期:2021-03-23
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