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MCL 通过稳定 NRF2 来抑制 ROS/AKT/ASAH1 通路，从而治疗他莫昔芬耐药性乳腺癌。

MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2.

机构信息

Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.

Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China.

出版信息

Cell Prolif. 2024 Nov;57(11):e13700. doi: 10.1111/cpr.13700. Epub 2024 Jun 26.

DOI:10.1111/cpr.13700
PMID:38924190
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11533064/
Abstract

Tamoxifen resistance is a common and difficult problem in the clinical treatment of breast cancer (BC). As a novel antitumor agent, Micheliolide (MCL) has shown a better therapeutic effect on tumours; however, little is known about MCL and its role in BC therapy. With tamoxifen stimulation, drug-resistant BC cells MCF7TAMR and T47DTAMR obtained a high oxidative status and Amidohydrolase 1 (ASAH1) was abnormally activated. The inhibition of ASAH1 rescued the sensitivity of resistant cells to tamoxifen. We found that MCL inhibited the expression of ASAH1 and cell proliferation, especially in MCF7TAMR and T47DTAMR cells. The high oxidative stress status of resistant cells stimulated the expression of ASAH1 by positively regulating AKT, which was restrained by MCL. MCL activated NRF2 by directly binding to KEAP1 and promoting the antioxidant level of tamoxifen-resistant (TAMR) cells. In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. In conclusion, ASAH1 mediates tamoxifen resistance in ER-positive BC cells. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/AKT signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR-BC.

摘要

他莫昔芬耐药是乳腺癌（BC）临床治疗中的一个常见且棘手的问题。米壳萜内酯（MCL）作为一种新型抗肿瘤药物，对肿瘤显示出更好的治疗效果；然而，关于 MCL 及其在 BC 治疗中的作用知之甚少。在他莫昔芬刺激下，耐药 BC 细胞 MCF7TAMR 和 T47DTAMR 获得了高氧化状态，酰胺水解酶 1（ASAH1）异常激活。ASAH1 的抑制挽救了耐药细胞对他莫昔芬的敏感性。我们发现 MCL 抑制 ASAH1 的表达和细胞增殖，尤其是在 MCF7TAMR 和 T47DTAMR 细胞中。耐药细胞的高氧化应激状态通过正向调节 AKT 来刺激 ASAH1 的表达，而 MCL 则抑制了这一过程。MCL 通过直接与 KEAP1 结合激活 NRF2，促进他莫昔芬耐药（TAMR）细胞的抗氧化水平。此外，MCL 的前药 ACT001 在临床前异种移植肿瘤模型中显著抑制了 TAMR 细胞的肿瘤生长。总之，ASAH1 介导 ER 阳性 BC 细胞中的他莫昔芬耐药。MCL 可以通过 NRF2/KEAP1 激活细胞抗氧化系统，并通过 ROS/AKT 信号通路抑制 ASAH1 表达，从而抑制细胞增殖。MCL 可作为治疗 TAMR-BC 的潜在药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/ff6e6142c626/CPR-57-e13700-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/16535ccc2294/CPR-57-e13700-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/64262e56429f/CPR-57-e13700-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/7a77b67d0f8f/CPR-57-e13700-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/55ea0edbdfd0/CPR-57-e13700-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/845eb3e48972/CPR-57-e13700-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/336cd76c361b/CPR-57-e13700-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/ff6e6142c626/CPR-57-e13700-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/16535ccc2294/CPR-57-e13700-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/64262e56429f/CPR-57-e13700-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/7a77b67d0f8f/CPR-57-e13700-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/55ea0edbdfd0/CPR-57-e13700-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/845eb3e48972/CPR-57-e13700-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/336cd76c361b/CPR-57-e13700-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8470/11533064/ff6e6142c626/CPR-57-e13700-g005.jpg

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