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Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and .发现一种靶向ULK1调节的三阴性乳腺癌细胞死亡的小分子以及…… （原文结尾不完整）
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Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.基于晶体结构发现一种新型合成的PARP1抑制剂（OL-1）及其在三阴性乳腺癌中的凋亡诱导机制
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Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts.血清素能系统拮抗剂靶向乳腺肿瘤起始细胞，并与化疗协同作用以缩小人乳腺肿瘤异种移植瘤。
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A small-molecule activator induces ULK1-modulating autophagy-associated cell death in triple negative breast cancer.一种小分子激活剂可诱导三阴性乳腺癌中与ULK1调节的自噬相关的细胞死亡。
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Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer.应激诱导的通过信号转导和转录激活因子3的表皮生长因子受体信号传导与三阴性乳腺癌的肿瘤进展
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Novel targets for paclitaxel nano formulations: Hopes and hypes in triple negative breast cancer.紫杉醇纳米制剂的新靶点：三阴性乳腺癌的希望与炒作。
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氟西汀通过eEF2K-AMPK-mTOR-ULK复合体轴在三阴性乳腺癌中诱导自噬性细胞死亡。

Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer.

作者信息

Sun Dejuan, Zhu Lingjuan, Zhao Yuqian, Jiang Yingnan, Chen Lixia, Yu Yang, Ouyang Liang

机构信息

Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou, China.

出版信息

Cell Prolif. 2018 Apr;51(2):e12402. doi: 10.1111/cpr.12402. Epub 2017 Nov 1.

DOI:10.1111/cpr.12402
PMID:29094413
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6528897/
Abstract

OBJECTIVES

Triple negative breast cancer (TNBC) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small-molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small-molecule agent for TNBC treatment and illuminate its potential mechanisms.

MATERIALS AND METHODS

Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP-LC3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine-induced autophagy and apoptosis. Western blotting and siRNA transfection were carried out to investigate the mechanisms of Fluoxetine-induced autophagy. iTRAQ-based proteomics analysis was used to explore the underlying mechanisms.

RESULTS

We have demonstrated that Fluoxetine had remarkable anti-proliferative activities and induced autophagic cell death in MDA-MB-231 and MDA-MB-436 cells. The mechanism for Fluoxetine-induced autophagic cell death was associated with inhibition of eEF2K and activation of AMPK-mTOR-ULK complex axis. Further iTRAQ-based proteomics and network analyses revealed that Fluoxetine-induced mechanism was involved in BIRC6, BNIP1, SNAP29 and Bif-1.

CONCLUSIONS

These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC, which will hold a promise for the future TNBC therapy.

摘要

目的

三阴性乳腺癌（TNBC）是一种复杂且具有内在侵袭性的肿瘤，预后较差，用于TNBC治疗的靶向小分子药物的发现仍处于起步阶段。在本研究中，我们旨在发现一种用于TNBC治疗的小分子药物并阐明其潜在机制。

材料与方法

使用甲基噻唑基四氮唑（MTT）法检测细胞活力。进行电子显微镜、绿色荧光蛋白-微管相关蛋白1轻链3（GFP-LC3）转染、单丹磺酰尸胺染色和凋亡检测以确定氟西汀诱导的自噬和凋亡。进行蛋白质免疫印迹法和小干扰RNA（siRNA）转染以研究氟西汀诱导自噬的机制。基于同位素标记相对和绝对定量（iTRAQ）的蛋白质组学分析用于探索潜在机制。

结果

我们已证明氟西汀在MDA-MB-231和MDA-MB-436细胞中具有显著的抗增殖活性并诱导自噬性细胞死亡。氟西汀诱导自噬性细胞死亡的机制与真核生物延伸因子2激酶（eEF2K）的抑制和腺苷酸活化蛋白激酶-哺乳动物雷帕霉素靶蛋白-unc-51样自噬激活激酶1（AMPK-mTOR-ULK）复合体轴的激活有关。进一步基于iTRAQ的蛋白质组学和网络分析表明，氟西汀诱导的机制涉及杆状病毒IAP重复序列6（BIRC6）、BNIP1蛋白、突触融合蛋白29（SNAP29）和Bif-1。

结论

这些结果表明氟西汀在TNBC中诱导凋亡和自噬性细胞死亡，这将为未来的TNBC治疗带来希望。